2018-19 ANNUAL REPORT TABLE OF CONTENTS Stem Cells and Cancer and Molecular Cell Cryo-EM Biology Cancer Epigeneticsand Experimental Therapeutics Chromatin and Epigenetic Gene Regulation Transcription and Gene Regulation Tumor Microenvironment and Metastasis Cancer Biology Cellular Dynamics Cancer CellBiology and Translational Research Cell Death and Cancer Genetics Cellular andMolecular Biology Repair & Genome Stability DNA Genome Instability & Chromosome Biology Cancer Stem Cells and Necroptosis and Molecular Biophysics Membrane Biochemistry Molecular Bioengineeringand Cancer Vaccine Today’s EDUCATION, Tomorrow’s DISCOVERIES in GrowthPartners Departments Supporting Computational Cancer Genomics Cell Signaling and Tumorigenesis Structural Biology ofMembrane Transport

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34 32 30 28 26 24 22 20 18 16 14 12 10 48 46 42 40 38 36 6 8 4 to Accelerating MISSION STATEMENT community, thesurrounding region andtheStateofMinnesota. forthebenefitof Austin and educationalexpertise asacenteroftechnical community worldwide.Italso serves fundamental knowledgeand disseminatesitto thescientific as intendedby itsfounders,TheHormelInstitutegenerates in medicineandagriculture. In pursuitofthismission, and provide educationinthebiologicalscienceswithapplications The missionofHormelInstitute isto conductresearch and MISSION STATEMENT CANCER ANSWERS

MESSAGE FROMTHEEXECUTIVE DIRECTOR Interim Executive Director Ann M.Bode,Ph.D. Sincerely, The HormelInstitute, UMN-foryour continuedsupport. I’m honored to asinterimexecutive serve director andI thankyou -onbehalfofall continued successthrough discoveries leadingto cancerprevention andhealthiercontrols. and ourgenerous community, weare fullycommittedto enhancingandmaintainingourquestfor fromStrengthened theUniversity by ofMinnesota,TheHormelFoundation, leadershipandsupport to where weare today. The HormelInstitute facultyandstaff to helpbuildTheHormelInstitute, University ofMinnesota, After joiningTheHormelInstitute in1999,I have had agreat and incredible journey with late fallof2019. ourmission.In fact,twomore scientiststo research further expert sectionswillbeaddedinthe and staff.We nowhave 19research sectionswithplansto continueto filltheinstitute’s labswith longer, healthierlives. TheHormelInstituteiscurrently comprisedof140faculty, researchers, We are focusedonacceleratinganswersto cancerandotherchronic diseasessopeoplecanlive technologies. the art cancerresearchers,expert astunningdesignforourcancercenter, and labsfilledwithstateof After twomajorexpansionsin11years, TheHormelInstitute ishometo someoftheworld’s oftheMasonicCancerCenter.research part centerandhighperforming Today TheHormelInstitute, University ofMinnesotaisaprominent cancerandchronic disease

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 3 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 4 at the heart ofseveral devastating,at theheart oftenfatal functioning. Dysfunction ofthesesystems lies membranes iscentralto proper physiological material transfer across cellular andorganellar membrane bilayer integrityandtightcontrol over of membraneprotein function.Maintenanceof pinpointing lipid/protein interactionsincontext focuson and biogenesis,withaparticular homeostasis, involved inmembranetransport, macromolecules andmacromolecular complexes techniquesto crystallography) primarilystudy andX-raybiochemical andstructural(Cryo-EM The Alam labusesacombinationof Summary Amer Alam, Ph.D. Structural Biology of Membrane Transport SECTION LEADER / ASSISTANT PROFESSOR (routinely achieving betterthan0.5 designed to obtainnear-atomic resolution with adirect electron detector, asetup a TitanKriosmicroscope combined a handfulofeliteinstitutionshousing The HormelInstitute ranksamongst and cancer. of neurodegenerative disorders, diabetes, from peroxisomal dysfunction)to arange and adrenoleukodystrphy (both stemming diseases suchasZellweger’s syndrome pathologies rangingfrom rare inherited Primary ResearchAreas: Primary 4) 3) 2) 1) Lipid andfattyacidmetabolism Lipid/protein interactions homeostasis Peroxisome biogenesisand processes Membrane transport

membrane protein dysfunction. therapeutics targeting diseasesstemmingfrom and inhibitors andcanaidinthedesignofnovel substrates, interactions withdrugs,transport obtaining moleculardetailsofmembraneprotein visualization Suchinsightisinvaluable in previously considered off-limitsto highresolution for targeting ofcomplexbiologicalproblems revolutionized structuralbiologyandallowed the functioningof­­­ visualization ofthemoleculardetailsunderlying nanometer resolution). Thisallowsforaccurate Mehedi Hasan,AmerAlam,JamesThompson FROM LEFTTO RIGHT: Research Specialties: 3) 2) 1) X-ray crystallography electronCryo microscopy Membrane protein biochemistry macromolecules andhas Please visit us at: https://www.nature.com/npjprecisiononcology/ - The journal also publishes a professionally written Editorial Lay toaccompany each research Summary which summarizes Article, the key issuesbeing addressed within the article - In addition to publishing original basic science, translational and clinical research articles, - Featured topics include cancer development and prevention, therapies that target specific cellularpathways, cancermetabolism andgeneticrisk factors. - According totheManaging Editor at Nature Research “Npj Precision Oncology has been exceptionally successful”. We have passed the first landmark of 25 peer-reviewed published - - The journal defines precision oncologyas cancer diagnosis,prevention, and/or treatment tailored specifically to the individual patient basedon their genetic and/or molecular profile. - - Springer Nature launchedthe journal npj PRECISIONONCOLOGY npj Precision Oncology fills the need of ajournal where both preclinical this rapidly advancing and earlyclinical studies canbepublishedtogether to help support field. npj Precision Oncology, is a new open access, international, peer-reviewed journal that publishes cutting edge scientific research in allaspects of precision oncology, from basic aimed tokeep readership at the vanguard of new discoveries in the field. perspectives, and review articles. Associate Editors to bring on board. which makesarticles, our journal eligible toapplyforinclusion in PUBMED, one of the first steps required to obtainanIMPACT FACTOR. We are also lookingfor 1-2 additional science to translational applications to clinical medicine. “npj with The Hormel Institute, University Precision ofMinnesota in partnership in Austin, Minnesota, United States. Oncology” npj Precision Oncology -also publishes case reports, brief communications,commentaries,

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 5 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 6 cytotoxic CD8+T-cells andahumoralresponse a cross-presentation pathway activate botha AAV-delivered tumorantigeneitherdirectly orby antigen presenting cells(APC) uploadedwiththe needle vaccination procedures. As aresult, local melanoma orprostate cancerusingstandard AAV vectors are injectedinto animalmodelof tumor specificantigencarried by thesenovel tors to develop anti-cancervaccine. Briefly, optimized adeno-associated virus(AAV) vec- We currently useourbioengineered capsid- Summary George Aslanidi,Ph.D. Molecular Bioengineering and Cancer Vaccine SECTION PROFESSOR LEADER / ASSOCIATE

emerging aPD1 therapy. delays solidtumorgrowth andsynergized with prevents metastatictumorspread, significantly capacity againstencodedantigen. Thisvaccine a AAV basedvaccine hassuperiorcytolytic against thetumor. We showedthat ourdesigned intracellular trafficking Improved Heparin binding

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system and redirect it to kill cancer cells.” from endosome HI loop escape

immune cells, especially with CD8+ T cells and immune cells,especiallywith CD8+Tcellsand of thetumorby inducingmassive invasion of vaccination changestheimmunelandscape and microscopic analysis. More importantly, and confirmedantigenexpression by flow nodes afterinvivo modelintramuscularinjection genesuchasGFPindraininglymph reporter able to trackdowndendritic cell(DC) carrying killing capacityinvivo model.We alsowere as result, demonstratedsuperiorAg-specific long-lasting anti-tumorimmuneresponse, precursor (CD 62L-/CD127+)cellswhichensure enhanced theformationofeffector memory both antigen-specificCD8+TandCD4+cells, significantly increased AAV mediated level of molecule traffickingsignals.Thismodification cassette by fusingantigenwithMHCclassI optimized AAVstudies wefurther expression and subsequentantigenpresentation. In current increase transductionefficiencyofthe APCs modifications intheAAV capsidsignificantly viral cancervaccine technologies:theprecise overcome ofpast manyoftheshortcomings capsid-optimized AAV basedsystem, whichhas in after asingleinjectionofAAV-based vaccine antigen-specific immune response isdeveloped Our research hasdemonstratedthatastrong in vivo model.We attributethisto ournovel George Aslanidi

activate/support immunecellsinfiltratingtumor.activate/support that target tumormicroenvironment andre- withothertherapies target vaccination inconcert studies to completelyeradicatetumor, ismulti- that weare planningto implementinourfuture Therefore,model survival. thepathforward delayed tumordevelopment andextendinvivo in combinationwithaPD-1treatment significantly aPD-1 therapy. Indeed, useAAV basedvaccination expression ofPD-1shouldsensitize tumorto infiltrated lymphocytesdisplaying increased NK cells.Consequently, weshowedthattumor-

into clinicalapplicationforhumansiswarranted. friends, butprovide critical data ensuring progress will notonlyhelpto extendthelife ofpeople’s best of ourvaccine onclinicallyrelevant dogpatients efficacy ofouranti-cancer vaccination. Testing most adequatepreclinical model to evaluate the similartogy very humans. Thismakes dogsthe and are developing cancer withclinicalpatholo- are exposedto thesameenvironmental factors, neous melanoma.Importantly, companiondogs nation approach incompaniondogswithsponta- Additionally, weplanto testouranti-cancervacci- Back row: Day, Andrew Noah Johnson Front row: KellyVanhooser, Karina Krotova, George Aslanidi FROM LEFTTO RIGHT: CD11c Bottom Microscopy analysis. Dendritic cell. Top analysis, Flowcytometry Figure 2:Bioengineered AAV 6vectors infect AAV-GFP-immunized Non-immunized + /MHC II +

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 7 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 8 by studyingthe structuralfeatures ofsphingo - physical basis forraftmicrodomain functionality viruses andbacteria.Earlyon, weinvestigated the for signalingkinasesandtarget sitesforcertain microdomains that functionasorganizing regions sphingolipids form‘raft’ In membranes,certain anchoring devices forselectmembranesincells. (e.g. C2-domains)thatactastargeting and membranes andprotein lipid-bindingdomains that shuttlesphingolipidsbetweenintracellular proteins includesphingolipidtransfer proteins membrane lipidsknownassphingolipids.Such Our research focusesonproteins that interactwith Summary Rhoderick Brown, Ph.D. Molecular Biophysics and Membrane Biochemistry SECTION LEADER / PROFESSOR

revealed howGLTPs recognize andbindglycolipids ferent glycolipids by X-ray diffraction. Ourfindings both inglycolipid-free formandcomplexed withdif- enabling determinationoftheirmolecularstructures bacterial expression systemsto purifytheproteins mouse) aswellplantsandfungideveloped from various mammals(humans, bovine, porcine, golipids. We thefirstcloningofGLTPs performed (GLTPs) becauseoftheirspecificityfor glycosphin- initially identifiedasglycolipid transfer proteins cells. Thesesphingolipidtransfer proteins were shuttling sphingolipidbetweenmembranesin help formandmaintain‘raft’microdomains by We alsostudy sphingolipidtransfer proteins that microdomains. organizing functionalityofsphingolipid-enriched identified physical features central to the lateral sphingolipids andsterols change. This research environment’ whenthecontentand structure of physical variations thatoccurwithinthe‘raft to development ofways to quantitatively assess of modelmembranelateralelasticitywhichled (UMN-Hormel Institute), enabledmeasurement out incollaborationwiththeH.L.Brockman lab balance approaches. Thelatterapproach, carried copy, calorimetry, NMR,and Langmuirsurface investigations relied onfluorescence spectros - interactions withotherlipidsinmembranes.Our lipids thatregulate theirlateralandtransbilayer sphingolipid levels and locations in cells of is fundamental importance for developing new therapeutic approaches to inflammation and programmed cell death by regulating “Unraveling how sphingolipid transfer proteins control treat diseases such ascancer .” tion withCharlesChalfant,Univ. SouthFlorida). over-accumulation inthetrans-Golgi(collabora- leadstodepletion inhumancellsby RNAi C1P UMN-Hormel Institute),andshowedthatCPTP microscopy (collaboration withTed Hinchcliffe, fluorescence malian cellsusingstate-of-the-art MSKCC), CPTPintracellularlocationinmam- of humanCPTP(collaboration withD.J. Patel, Nature, structural characterization wereported phosphate (C1P) transfer proteins (CPTPs).In GLTP members,ceramide-1- superfamily Recent studieshave ledto discovery ofnew attheRussianAcademy ofScience. Chemistry kovsky attheShemyakin Institute ofBioogranic bioGUNE (Derio/Bilbao,Spain)andJ.G.Molot- Cancer Center(MSKCC), L.MalininaatCIC with D.J. Patel atMemorialSloanKettering Research. Ourworkbenefitedfrom collaboration Journal, Biochemistry, andJournalofLipid The JournalofBiologicalChemistry, Biophysical are publishedinNature, PLoSBiology, Structure, GLTPH domainofhumanFAPP2. Thefindings glycolipid selectivityoffungalGLTP andthe iii) thestructuralbasisformore focused in glycolipid bindingandmembraneinteraction; function played by intrinsictryptophan residues to accommodate different glycolipids; ii)the shedding lighton:i)GLTP bindingsiteadaptation to accomplish intermembrane transfer by Rhoderick “Rick” Brown

conditions, i.e. cancer, diabetesanddementia. and otherinflammation-associated pathologic ies couldhelpdevelop new treatments forsepsis phospholipidsineLife.target Ourdiscover certain - into to theselectionmechanismusedby cPLA2α inflammation. We recently publishednewinsights sequently helpreverse andresolve sepsis-related caninitiallypromotestanding howcPLA2α butsub- arephospholipase A2 (cPLA2α) aimedatunder- production. Ongoingstudiesofhumancytoplasmic acid anddownstream pro inflammatory eicosanoid phospholipase A2 actionto generatearachidonic The C1Pover-accumulation triggerscytoplasmic Current researchprojects: 4) 3) 2) 1) Transfer Protein (CPTP): New Regulation ofCeramide-1-Phosphate Transfer Proteins vention Potential by Sphingolipid Initiation andProgression: Inter- Inflammation inBreast Cancer C1P Interaction inSepsisResolution The Functional RoleofthecPLA2α/ Proteins inEukaryotes Function ofSphingolipidTransfer Structural Characterizationand Cancer Therapeutics Strategy forEnhancingBreast

tions, pleasevisit thefollowingwebsites: research andscientificpublica- activities, expertise Hormel Foundation. For more detailsregarding our Minnesota’s Paint-the-Town PinkInitiative, andThe Institute, NIHNationalCancerInstitute, Southern LungSciences, NIH NationalHeart andBlood from NIH National Institute ofGeneralMedical proteins whichhasbeenfueledby financialsupport for continuingstudiesofGLTP, CPTP, andrelated exciting research progress emphasizes theneed apeutic approaches to treat otherdiseases.The tively destroy cancercellsandleadto newther- composition. Suchstrategiescouldhelpselec- for targeted manipulationofcellularsphingolipid likely facilitatetheirdevelopment asnano-devices Our studiesofGLTP proteins superfamily will (IL1B andIL18). masome assemblythatdrives interleukinrelease an endogenousregulator ofautophagy andinflam- Autophagy, showingthathumanCPTPfunctions findings stimulated in recent studies reported mide levels to drive programmed celldeath.The development by severely alteringC1Pandcera- Shrawan Mishra (not pictured) Yong-guang Gao, Lucy Malinina, Rhoderick (Rick)Brown, FROM LEFTTO RIGHT: of acd11 gene impairs plant of acd11geneimpairsplant C1P andphytoC1P. Disruption fold evolved to bindandtransfer revealed thatACD11 isaGLTP- John Mundy(Univ. Copenhagen) with D.J. Patel (MSKCC) and incollaboration Cell Reports X ray structures publishedin In studiesofplantCPTP, ACD11,

rhoderick-e-brown https://experts.umn.edu/en/persons/ publications): and (REBresearchexpertise Experts-UMN https://orcid.org/0000-0002-7337-3604 ORCID ID(REB): rhoderick-e-brown/ https://www.hi.umn.edu/portfolio-items/ REB Labresearchactivities: Other professionalactivities: • • • • • • • •

Journal ofLipidsEditorial Board &Physics ofLipids,EditorialChemistry Board reviewer Japan SocietyforPromotion ofScience National ScienceFoundation reviewer consultant Ad hocNIH StudySectionmemberand Biophysical Society Membrane Structure &AssemblySubgroup, Molecular Biology and American SocietyforBiochemistry Biophysical Society

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 9 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 10 Ilana Chefetz Menaker, Ph.D. Cancer Stem Cells and Necroptosis SECTION LEADER / ASSISTANT PROFESSOR Stem cells taking into consideration that tumor cells “We are trying to identify and characterize novel targeted therapies that target specificallyCancer are heterogeneous.” balance isessentialto triggercancercell cell proliferation ornecroptosis/apoptosis proteins. Thus,elucidationofnecroptosis/ due to elevated expression ofanti-apoptotic overcome drugresistance incancercells cell deathintumors,canpotentially the otherhand,drugs,inducingnecroptotic prevent ormitigateundesirable celldeath.On infections; thustargeting necroptosis will disorders, andviral ischemia andheart of diseasesincludingneurodegeneration, Necroptosis inpathogenies participates that necrosis canoccurinregulated manner. ischemia. However, recent studiesnowreveal associated withcellinjury, inflammation or non-regulated anduncontrollable event morphology andfeatures thoughto bea death pathway. Celldeathwithnecrotic is arecently identifiednovel regulated cell Cell programmed necrosis ornecroptosis therapies andprevent recurrent disease. (necroptosis) inorder to designtargeted aspects ofcellprogrammed necrosis Our labstudiesthemolecularandmetabolic Summary Ilana Chefetz Menaker followed by theirdownstream target MLKL. proteins 1and3(RIPK1 andRIPK3) the kinaseactivityofReceptor-interacting pan-Caspase inhibitor ZVAD-FMK, requires TNF-α whileCaspasesare inhibited using studied kindofnecroptosis isinitiatedby such asischemiaorinflammation. Themost death orprevent pathologicalconditions Figure 1: Transmission Electronic Microscopy ofmitochondria. Current researchprojects: 3) 2) 1) characterization characterization cancer cell,purificationand Effect ofexosomes onovarian ovarian cancerstemcells preferable source ofenergy of asa Oxidative Phosphorylation Novel compoundsthattarget inhibition ofALDH1A andMEK1/2 grade serous ovarian cancer-dual Novel combination therapy inhigh

unknown orbeingdisputed. many moleculardownstream events are membranes. Despitenecroptosis importance, by disintegrationofmitochondrial andplasma micro-complex (20 MDa)necroptosome followed Necroptosis execution involves formationof capacity ofCancer Stem cells. Figure 2:Selfrenewal anddifferentiation Invited seminars: 2) 1) of Chicago,OBGYNdepartment Stem-Like cells.June, 2018.University Induces Necroptosis inOvarian Cancer A Novel Pan-ALDH1A Inhibitor Mayo clinic,Ovarian cancerspore group cells. September21st,2017. Necroptosis inOvarian CancerStem-Like A Novel Pan-ALDH1A Inhibitor Induces Mikhail Chesnokov, Imran Kha Willrodt, Back row: Mary Ilana Chefetz Menaker, GollaNaresh Front row: Anmbreen Jamroze, FROM LEFTTO RIGHT:

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 11 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 12 in non-disjunction disorders, cancers, andfibrosis. chromosome segregation andgenome instability sequences, and therole theseelementsplay in that modulatecentromere function oncentromere the epigeneticinteractionsof chromatin factors structure andevolution ofcentromere sequences, defects. I aminvestigatingsis, cancersandbirth the mis-segregation andinstability, hallmarksoffibro - of centromere functionresults inchromosomal mosomes duringcelldivision.Destabilization responsible forthecorrect segregation ofchro- genomics. Thecentromere isthe structuralunit genome. I have aspecialinterest incentromere ing thefunctionofrepetitive areas ofthehuman My research interests are focusedoninvestigat- Summary Rafael Contreras, Ph.D. Genome Instability&Chromosome Biology SECTION LEADER / ASSISTANT PROFESSOR sequences, theirgenetic variation inhuman We have studiedthecomposition ofcentromeric oped molecular tools to studytheseelements. arrays ineachhumanchromosome anddevel- have identifiedmarkers formultiplecentromere of aCareer Development Award K22by NCI we that assemblethekinetochore. With thesupport repeats recruit centromeric chromatin factors investigators hasindicatedthatspecificalpha ics, asrecent evidence from ourlabandother forhumangenom- important maps. Thisisvery sequences to fillthegapsofhumancentromere In thelastyears I have annotatedcentromere unique structure ineachhumanchromosome. human centromeres andthatare foundina are themainarrays ofrepetitive elements in elements, theso-calledalpharepeats, which characterizing othercentromere repetitive areas ofthechromosomes. We are also genetic materialatrateshigherthanother reshuffling duringevolution andexchanged centromeres have beenundercontinuous roviruses revealed that,surprisingly, human analysis ofcentromere K111andK222ret - a lastfrontier ofhuman genetics.Sequence nature oftheseareas, andtherefore, remain ficult to annotatebecauseofthe repetitive man genomethathave beenextremely dif- centromere genomics,regions ofthehu- to studyhuman giving ustheopportunity 2013; Zahnetal.2015).Thesefindingsare the humangenome(Contreras-Galindo et al. K222, whichreside inthecentromeres of family, thetypesK111and inparticular of endogenousretroviruses oftheHERV-K discovered andcharacterized thousands human genome.Duringthesestudies,we repetitive elementsthatcomprise8%ofthe gating HumanEndogenousRetroviruses, My research hasbeenfocusedoninvesti- Human CentromereGenomics

sequences inthecentromere flanksthatkeep proteins thatrecruit kinetochores, aswell arrays ineachhumanchromosome bind this task.We have elucidatedwhichcentromere ChIP-PCR andChIP-Seqmethodsto assess ofchromosomes. Wepartition have developed and H3K9me3;factors thatensure thecorrect cell divisionthrough epigeneticfactors HP1 the cohesiveness ofsisterchromatids during centromere sequencesare essentialto maintain bly. Further, weare alsocharacterizingwhich inkinetochoreso on)that participate assem- centromere proteins (CENP-B, CENP-C,and centromere markCENP-Aandrecruit other packed into nucleosomesby thehistone 3-like arrays ineachhumanchromosome are We are studyingwhichcentromere alphoid Segregation Centromere Function and Chromosome these diseases. tromere functionandchromosome instabilityin study theeffect ofcentromere instabilityincen- scleroderma fibrosis andcancers. We plan to mis-segregation suchas trisomy21, aswell ity indisorders characterized by chromosome evidence ofextensive centromere instabil- DNA Using thesemarkers, wehave identifiedstartling each humanchromosome except forChr19. We have discovered centromere markers for modulate centromere assemblyandfunction. in thecentromeres ofeachchromosome that populations andidentifiedfunctionalelements Primary ResearchAreas: Primary 3) 2) 1) Genetics andGenomics Molecular Biology Chromosome Biology

ingly, theloss ofcentromere retroviruses K111 exhibit profound centromere instability. Interest- cells, whichdisplay extensive chromosome ploidy, and teratocarcinoma. Thissuggeststhatcancer ian, andprostate cancer, lymphoma/leukemia, most cancercellsstudied,including breast, ovar- centromere arrays are found inthegenomeof detected inhealthycells,significantly smaller in contrast to thesize ofcentromere elements tromeres, that wemadetheobservation Using moleculartools to studyhumancen - Centromeres incancer disease. findings inthestudyofhumancentromeres in These technologieswillgenerateunprecedented centromere mutatesandbecomesinactive. lishment ofneo-centromeres astheoriginal ectopic chromosomal armswiththeestab- increased occupancyofcentromere markson therefore, chromosomal segregation. We predict ing centromere/pericentromere architecture, and and/or H3K9me3toward otherelements,affect- will displacetheoccupancyofCENP-A, CENP-B, anticipate thatmutationofcentromere elements deposition ofcentromere chromatin marks.We centromere sequencewillaffect thebalanced The hypothesisisthatmutationsinthe centromeres inotherareas ofthechromosomes. arrays thatremain intactand/orcreate neo- deposition ofkinetochores towards juxtaposed elements aswehave seenindiseasealterthe We are studyingwhethermutationsincentromere employing CRISPR Cas9to mutatecentromeres. centromere sequencemutationsarise.We are well ascohesionfunctionisinfluencedwhen deposition andassemblyofcentromeres as to understandhowthe important It isvery for publicationinthejournal GenomeResearch. are inarecent reported manuscriptaccepted sister chromatids together. Thesenovel findings

with trisomy21. We are creating centromere types seenindifferent cellstypesofpatients the development ofdisease-associatedpheno- mutations intrisomy21development andalsoin segregation to studytheeffect ofcentromere 21 ing IF-FISH andotherassays for chromosome We are alsousingcytogenetic analysis,includ- es incentromere functionandChr 21 segregation. characterize theeffect ofthesegeneticimbalanc- (hESc) usingCRISPR Cas9technologyinorder to stemcells normal cellsandhumanembryonic tions inthecentromere ofChr21inkaryotypically junction disorder. We are creating specificdele- instability isassociatedwiththisChr21non-dis- chromosomes, suggestingthatcentromere 21 with trisomy21(Downsyndrome) butnotother core andpericentromere ofChr21inindividuals tromere instabilityspecificallyinthecentromere We have evidence foundextraordinary ofcen- Centromere defectsinTrisomy 21 centromere defects. nude We invivo willexpand theseobservations using ation, differentiation, andcelltransformation. instability/aneuploidy, cellgrowth andprolifer- the effect ofcentromere mutationsingenome and aneuploidyseenincancer. We are studying role ofcentromere deletioningenomeinstability tion. Thesestudieswillhelpusto understandthe sembly andfunctionchromosome segrega- effect ofcentromere instabilityoncentromere as- CRISPR Cas9andCre-LoxP to determinethe cells inchromosomally normalhuman cellsusing recreating thesemutationsoccurringincancer mutant centromere retroviruses. Currently, I am tromere retroviruses resulted inselectionofnew K111s. In othercancers,deletionofsomecen- was theresult ofrecombinational deletionamong leukemia/lymphoma (ATL) celllines,forexample, at thepericentromeres, specificallyinadult T-cell in vivo modelstransplantedwithcells the Scleroderma Foundation. promising findings.This by research issupported Scleroderma isacentromere diseasewithvery Scleroderma patients,weare clarifyingwhether an immuneresponse to centromeres isseenin genetics andepigeneticsdefects, together with antibodies inthesepatients.As bothcentromere that correlate withtheproduction ofcentromere defective inScleroderma fibroblasts, afinding seen thatcentromere epigeneticfactors are also mosomes inScleroderma fibroblasts, wehave finding ofcentromere instabilityofspecificchro- tromeres andkinetochores. Besidesthenovel fundamental forthediscovery ofhumancen- directed to centromeres. Theseantibodieswere as patientswiththisdiseaseproduce antibodies on thefunctionofcentromeres inScleroderma Last butnotleast,wehave aspecialattention Centromeres inScleroderma Genome Research. Some ofthesefindingsare showninthejournal in trisomy21braindevelopment andAlzheimer. cells to studythe effect ofcentromere instability 21 mutationsiniPScthatdifferentiate into brain Research Specialties: 5) 4) 3) 2) 1) Deep-sequencing ofcentromeres CRIPR Cas9andCre-LoxP Genome editingofcentromeres using Centromeres instabilityandRepairof DNA Genomics ofHumanCentromeres and Cancer Pathogenesis ofScleroderma Fibrosis

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 13 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 14 for selective killing of cancer cells, without harming highly dysregulated creating aunique opportunity cancer development and treatment. Robust and “DNA repair plays an active and critical role in our cells from cellular transformation. In many different cancer types DNA repair processes are mechanisms of tumor suppression and identify identify and suppression tumor of mechanisms novel targets in personalized cancer therapy.” tightly regulated DNA repair systems protect the normal cells. Our studies reveal will new Wioletta Czaja,Ph.D. Repair&Genome Stability DNA SECTION LEADER / ASSISTANT PROFESSOR Wioletta Czaja genome ismaintainedandregulated in to understandhowstabilityofthehuman The long-termobjective ofourresearch is involved inmutagenesisandcarcinogenesis. the goalofuncovering novel mechanisms bases,with of damagedandmodifiedDNA direct detection,andgenome-wideprofiling development ofnewapproaches enabling damage repair. We are alsoworkingon and chromatin-based regulation ofDNA with aspecialfocusontheepigenetic mechanisms protecting genomicintegrity, under-stood. We investigate thefundamental leading to genomicinstabilityare notwell repairDNA processes. Themolecularevents resulting from deficientordysregulated of mutations,chromosomal rearrangements), levels ofgenomicinstability(high frequency Nearly allformsofcancercontainsignificant Summary stability. on mechanismsofgenome Figure 1.Integrative research both thedevelopment andtreatment ofcancer. by alkylating agents play significant roles in modificationsinduced anti-cancer drugs.DNA adductsareDNA inducedby commonlyused cellular metabolites.Someofthemosttoxic alkyl numerous environmental carcinogens and lesions thatarisefrom exposure ofcellsto adducts are cytotoxic andmutagenicDNA adducts.Alkyl DNA of mutagenicalkylDNA ADA-SMRT enablingdirect, genome-wideprofiling prevention; Development ofnewmethodology New toolsincancerriskidentificationand cell lines. (yeast-Saccharomyces cerevisiae) andhuman and genomicsusingfungalmodelorganisms biochemistry, cellandmolecularbiology, genetics We approaches employ complementary in cancer therapy andpersonalized medicine. knowledge to promote advances innovel anti- various cellsandtissues,to applythisnew

and response to chemotherapy. individual differences incancerpredisposition human genomeandbetterunderstandingofthe a frameworkforfuture investigation of the genomes.Thisresearcheukaryotic willprovide adductsin mapping ofvarious alkylDNA time, direct andsimultaneoushighthroughput ADA-SMRT sequencingwillenable,forthefirst SMRT sequencing.Thedevelopment DNA of carcinogenic adducts(ADA) alkylDNA by using a newmethodologyenablingdirect detectionof we are workingondevelopment ofADA-SMRT, Icahn SchoolofMedicine,Mt.Sinai,NewYork, with theUniversity ofGeorgia, Athens, GA and adduct formationandrepair. In collaboration epigenomic landscapeofthecell)influenceinitial of chemotherapy agents,orthegenomic and investigate howfactors (such asmodifications genome-wide profiles oftheselesions and it isimperative to beableto examinecomplete, mutagenesis, cancerdevelopment andtreatment, adductscontributeto understand howalkylDNA predispose cellsto malignanttransformation.To adducts inducedby commonalkylatingagents oncogene orTP53tumorsuppressor gene.DNA for malignanttransformation,suchas H-ras such asthoseoftenfoundingenescritical lesions caninduceG→ Persistent andinefficiently repaired alkylDNA Primary Research Areas: Primary 6) 5) Mutagenesis 4) Carcinogens 3) 2) 1) Genome technologies Alkylating agents Chromatin remodeling damageand repairDNA A transition mutations A transition mutations

imbalanced BER in SWI/SNF-deficient cancers. imbalanced BERinSWI/SNF-deficient cancers. loss ofSWI/SNF functionmightleadto aberrant, ed in20%ofcancers,raising thepossibilitythat human SWI/SNF remodeler isfrequently mutat- human cancercellsdeficient intheSWI/SNF. The in yeast cells.Currently weinvestigate theBERin tin remodeler adducts andtheBERofalkylDNA SNF (SWItch/Sucrose Non-Fermentable) chroma- we identifiedalinkbetweentheessentialSWI/ sis andcontributeto chemoresistance. Previously (BER imbalance)isthoughtto drive carcinogene- formation. Dysregulation oftheBERpathway accumulation ofmutationsandmalignanttrans- adductsandprotectionDNA ofcellsfrom the ed BERisessentialfortheefficient repair ofalkyl studied. Inhumancells,robust and tightlyregulat- regulation ofBERhas beensubstantiallyunder- repairother DNA pathways, thechromatin-based novel anti-cancerdrugdiscovery. However, unlike pathway inallcells,andisanattractive target in is considered afundamental tumor suppressor sion Repair(BER). TheBaseExcision Repair(BER) repair damage viaBaseExci ofthealkylated DNA - chromatin remodeling factors inmodulatingthe this area focusesoninvestigating therole ofthe hibitory to repair DNA processes. Ourresearch in ly compactedchromatin, whichisinherently in- repairDNA isaccomplishedin thecontextofhigh- repairthe DNA fieldis to understandhowefficient genotoxic agents.Oneofthemajorchallengesin mechanisms inmodulationofcellulartoxicity to of geneticandepigenetic(chromatin-based) tween different tissues,highlightinginvolvement considerably betweenindividualsandbe- vary regulation repair. ofDNA repair DNA capacity suppression; Epigenetic(chromatin-based) Identification ofnewmechanisms oftumor

(PI: CzajaW) R21 NIH NIEHS 1R21ES02854901A1 Funding: therapy ofSWI/SNF-deficient cancers. agents, andwillprovide newinsightsforimproved the humancellsto chemotherapy alkylating mechanisms thatmodulatetheresponses of These studieswillelucidatenewchromatin-based 3) 2) 1) Current projects: • ADA-SMRT Development ofnewmethodology • • Excision Repair(BER) Chromatin-based regulationofBase • HELLS ingenomestabilityandcancer Role ofchromatinremodelerLSH/

chemotherapy-induced DNA adducts chemotherapy-induced DNA Genome-wide profiling ofthe tumor suppressor New linkbetweenBERandSWI/SNF and treatment BER balanceincancerprevention in repair ofheterochromatin domains Investigating newrole ofLSH/HELLS

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 15 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 16 cancer prevention andtherapy. in cancerdevelopment, aswellagentsfor mechanisms, wecontinueto discover key events death worldwide.Byfocusingonitsmolecular Cancer isoneoftheleadingcauseshuman Summary Zigang Dong,M.D., Dr. P.H. Cellular and Molecular Biology MCKNIGHT PRESIDENTIAL PROFESSOR IN HORMEL-KNOWLTON PROFESSOR CANCER PREVENTION SECTION LEADER

“Cancer one is of the leading causes of human death worldwide. By focusing in cancer development, aswell asagents for cancer prevention and therapy.” on its molecular mechanisms, we continue to discover key molecular events

could significantlyinhibitPDX tumorgrowth. upregulated withCELF2.CELF2genedelivery with PTEN. PTEN phosphatase activity is with PTEN.PTENphosphataseactivityis with PREX2andreduces itsassociation tumor suppressor incancer. CELF2interacts binding protein, cooperateswithPTENasa PREX2 andrevealed that CELF2, anRNA PTEN phosphataseactivityisinhibitedby homolog (PTEN) protein. Studiesshowed that the dual-specificityphosphataseandtensin of proliferation andisnegatively regulated by intheregulation signaling pathway isimportant The phosphoinositide3-kinase(PI3-K)/Akt metastasis to thelung. 5-fluorouracil (5-FU) inhibitedcoloncancer of PRPK,andshowedthatFA combinedwith fusidic acidsodiumsalt(FA) asaninhibitor IV, compared withstagesI andII. We identified with latestagesofmetastasis,III and expression levels ofp-PRPK are associated promotes coloncancermetastasis. Higher cell-originated protein kinase(TOPK) and by T-LAKkinase (PRPK) isphosphorylated demonstrated thatp53-related protein for patientswithsolidmalignancies.We Metastasis isthemajorcauseofdeath in cancerdevelopment andmetastasis 1. Discovery ofkey molecularevents

bromide (Zemuron two PRPKinhibitors, FDA-approved rocuronium (SSL)-induced skincarcinogenesis. We identified and conferred resistance to solar-simulatedlight down ofTOPK inhibitedPRPKphosphorylation protein by TOPK. thatisphosphorylated Knock- We thatPRPKisa novel reported oncogenic for cancerprevention 2. Discovery ofnovel targetsandagents ate (Betaderm target forlungcancerprevention andtherapy. suggests thatTRAF1 offers acandidate molecular probability.with patientsurvival Overall, ourwork and expression level wasinversely correlated pressed inhumanlungcancercellsandtissues (TNFR)-associated factor 1(TRAF1) isoverex- We thattumornecrosis report factor receptor studies focusingonLTA4H inhibition inCRC. further of bestatinefficacyinCRCandsupport models. Theseresults demonstrate evaluation tatin effectively inhibitedtumorigenesisinvivo group compared withtheuntreated group. Bes- signaling pathway inadrug(bestatin)-treated tients showedasignificantdecrease inthe LTA4H probability.survival Samplesfrom 13CRCpa- expression ofLTA4H alsoassociatedwithCRC plays arole incolorectal cancer(CRC). High The leukotrieneA4 hydrolase (LTA4H) pathway squamous cellcarcinoma (cSCC) development. compound decreased SSL-induced cutaneous ® ) andtopical applicationofeither ® ) orbetamethasone17-valer- Zigang Dong

Aurora kinasesplay acrucialrole inmitosis and sive malignanciesoftheupperaerodigestive tract. Esophageal cancer(EC) isoneofthemostaggres- for cancertherapy 3. Discovery ofnovel targetsandagents expressing high levels ofAKT. were verified inpatient-derived xenograft tumors bition ofESCCcellgrowth. Theeffects oforidonin oridonin and5-FUorcisplatin enhancedtheinhi- of esophagealcancercells. A combination of blocking AKT kinaseactivityandinhibitedgrowth AKT andsuppresses proliferation ofESCCby Oridonin,anaturalcompound,isaninhibitor of signaling pathways to inhibitgrowth. extracellular signal-regulated kinase1/2(ERK1/2) kinase 1/2(MEK1/2) andsuppressing the directly targeting themitogen-activated protein presses esophagealcancercell(ESCC) growth by Purpurogallin isanaturalcompoundthatsup- of osteosarcoma cellgrowth. ed thatHOI-07 treatment suppressed thegrowth Results ofaxenograft invivo modelstudyindicat- a compound,HOI-07, as aspecific Aurora Bkinase. compared withnormalbonetissue.We developed Aurora Bkinaseisoverexpressed inosteosarcoma tumor affecting boneandprognosis poor. isvery humanmalignant Osteosarcoma istheprimary agent againstesophageal cancer. APIO-EE-9 couldbedeveloped asatherapeutic patient-derived xenograft tumorssuggestingthat significantly decreased thesize ofesophageal with bothAurora A andB.Importantly, APIO-EE-9 death ofesophagealcancercellsby interacting APIO-EE-9, whichinhibitsgrowth andinduces we identifiedanovel compound, referred to as

found thatAshitaba chalcones,4-hydroxyderricin overactivated, resulting inuncontrolled growth. We MEK/ERK andPI3-K/AKT signalingpathways are peutic treatments. In melanoma,both theBRAF/ the skinthatlackseffective preventive andthera- Malignant melanomaisan aggressive tumorof signaling proteins. AURKA andRSK2activitiestheirdownstream tric cancergrowth by directly bindingandinhibiting (AURKA) andRSK2inhibitor thatsuppresses gas- Gossypin isaflavone, that isan Aurora kinaseA Third Row: JunshengZhu,Jinhua Wang, Souren Paul, Rathore, Joohyun Ryu,Moeez Xiaoyu Chang,TianshunZhang,Wei-Ya Ma,RajaDey Second Row: Teri Johnson,XinliMa,JianLi,Faisal Aziz,Yifei Xie,SeungHo Shin, Tressie Kinney, KeYao, AbhijitChakraborty, Humberto deVitto Muhammad Azeem Saeed First Row: Tara Adams,HanyongChen,HisaeYoshitomi, ThiMyLe Le, Zigang Dong, EunmiriRoh, QiushiWang, Kanamata Reddy, FROM LEFTTO RIGHT: against melanoma. ing chemopreventive ortherapeuticagents death ofmelanomacellsandthusare promis- both BRAFV600E andPI3-Kleadingto the melanoma development by directly targeting (4HD) andxanthoangelol(XAG), suppressed

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 17 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 18 while sparingnormal cells.Accordingly, wehave pounds thatselectively target humancancercells design to discover novel smallmolecularcom- utilizing computationaldrug target screen and selectively translatedinsitutumorigenesis;and and structurallyunderstand how oncogenesare X-ray to andCryo-EM functionally crystallography cluding genomeeditingtechnology(CRISPR-Cas9), metastasis contribute to tumorinitiation, progression and the geneticchangesidentifiedincancerpatients neered My research labhasbeenutilizinggeneticengi- Summary Yibin Deng,M.D., Ph.D. Cell Death and Cancer Genetics SECTION LEADER / I.J.HOLTON PROFESSOR in vivo modelsto address whetherandhow in vivo; utilizingmultipleapproaches in-

androgen receptor (AR) signalingaxistherapy. resistance to thesecondgenerationofanti- exist forCRPCpatientswhohave developed cancer (CRPC). Currently, notherapeuticoptions aggressive castration-resistant prostate resistance to ADT andprogress to amore these prostate cancersinvariably develop metastatic prostate cancer. Unfortunately, remains thegoldstandard-of-care therapy for (ADT) by surgical and/orchemicalcastration United States.Androgen deprivation therapy related deathsinmenafterlungcancerthe is thesecondleadingcauseofcancer- Prostate cancerstrikes oneinsixmenand castration-resistant prostatecancer metabolic targetforcurrentlyincurable 1. Discovering agene-regulated cancer cells. to selectively andeffectively kill a means as serve cancers thatcan of aiming to identifytheAchilles’ heel in vivo models,andclinicalpractice biology, pathology, preclinical genetic medicinal chemistry, structural from theareas ofcancerbiology, team thatbringstogether expertise established astrong collaborative “Our studies reveal will whether and how the genetic changes identified in cancer patients lead to tumorigenesis vivoin and identify effective strategies targeting cancerous cells

while leaving normal cells untouched.”

Figure 1. Anovel 1. Figure

Figure 1.Anovel therapeutic

strategy for CRPC strategy forCRPC demonstrate thatco-targeting theHK2-mediated tumor growth invivo; Pharmacologically, we mediated Warburg effect isrequired forCRPC axis; Genetically, wedemonstrate thatHK2- thesis) through AKT1-mTORC1-eIF4A1-mediated translation(proteinenhances HK2mRNA syn- degradation;and(c) PTEN lossselectively mRNA through inhibitionofmiR143-mediated HK2 gene; (b) p53deficiencyincreases HK2mRNA pation attheAR bindingsites(ARBS) withinHK2 transcriptionthrough(HK2) mRNA direct occu- that (a) ARamplificationincreases hexokinase2 amplification; Mechanistically, wedemonstrate CRPC harboringPTEN loss/p53mutationorAR glucose-6-phosphate, isselectively inducedin step ofglycolysis glucoseto by phosphorylating 2) protein, whichcatalyzes theirreversible first TP53. Ourlatestdata showthatHK2(hexokinase harboring co-deletionor-mutationofPTENand cation whileadditional30%ofCRPCpatients bothPTEN carrying Clinically, approximately 30%ofCRPCpatients therapeutic strategy for CRPC strategy for therapeutic mutationandAR amplifi-

Yibin Deng

Puja Singh,YibinDeng,ZhengboSong,Yu Wang, Peng Li FROM LEFTTO RIGHT: oncogene mRNA translationin cancer cells. oncogene mRNA eIF4A andeIF4Gplays acrucialrole ininitiating chemical studies suggestedthatinteraction of three subunits eIF4E, eIF4A and eIF4G. Bio- (eIF4F) heterotrimeric complexcomposedof translationinitiationfactorthe eukaryotic 4F initiation, whichispredominantly mediatedby cess, butitislargely achieved duringtranslation occurs atmultiplestepsofthetranslationpro- translationregulation in tumorigenesis.mRNA tion into oncogeneprotein plays acrucialrole transla Dysregulated (mRNA) messengerRNA translation intumorigenesis 2. UnderstandingoncogenemRNA effective strategyforcurrently incurable CRPC. HK2-mediated Warburg effect asaselective and recent thattargeting findingsstrongly support in vivo models( and remarkably inCRPC extendshostsurvival (HCQ) efficientlykillsHK2-dependentCRPCcells toxic quinolone-derivative hydroxychloroquine agy withFDA-approved chloroquine (CQ) orless okinase inhibitor) and ULK-1-dependent autoph- Warburg effect with2-deoxyglucose (2-DG, ahex- Figure 1).Taken together, our

Figure 2. Crystal Crystal 2. Figure

- man eIF4A/eIF4G ( successfully solve thecomplexstructure ofhu- We have to beenutilizingx-ray crystallography phy, Cryo-electron microscopy and (cryo-EM), Currently, weare combining X-ray- crystallogra synthesis and inhibit tumordevelopment invivo. cells to selectively blockoncogeneprotein disrupt theeIF4A/eIF4G interactionincancer discovery ofsmall-moleculecompoundsthat vivo. Ourstudiesthusprovide astructure-based to thecomplexformationandtumorigenesis in studies reveal thecrucialresidues contributing Figure 2. Crystal structure of human structureofhuman Figure 2.Crystal human eIF4A human of structure eIF4A/eIF4G complex eIF4A/eIF4G complex ). Site-mutagenesis Figure 2).Site-mutagenesis eIF4A eIF4G

. Institute ofNIH (R21s andR01s). Hormel Foundation andNational Cancer the grantsfrom TheUniversity ofMinnesota, Our research projects by are wellsupported tively killhumanbreast/prostate cancercells. and stimulatetheimmunepathways to effec - mere dysfunction-driven tumorigenesisinvivo dissect therole ofimmuneresponse intelo- these novel breast/prostate cancermodelsto immune pathway invivo . We have beenutilizing age response (DDR)-STING/TBK1-IRF3 innate dam- uncapping, whichinturninducesDNA prostate cancermodelsharboring telomere tory hasbeenengineeringanovel breast and (telomere uncapping).Ourlabora - perturbed ing proteins –termed“shelterin complex”–are - when componentsofthetelomericDNA-bind telomere or attrition(telomere shortening) telomeres couldariseeitherfrom progressive mosome end-to-end fusions.Dysfunctional andpreventas aberrantdamaged DNA chro- chromosomal endsfrom beingrecognized Telomeres are nucleoprotein capsthatprotect immune responseintumorigenesis telomere-induced DDR-STINGinnate 3. Dissectingtheroleofdysfunctional leads to tumorigenesis. translation,which selective oncogenemRNA otic translationinitiationcomplexinvolved in biological studiesto- decipherhowtheeukary Study Section; Reviewer forScientific Journals Standing Member, National CancerInstitute Other professionalactivities: /eIF4G complex complex /eIF4G

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 19 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 20 mechanisms of ciliary loss,andwhatare the mechanisms of ciliary cells; therefore, to weare trying understandthe found thatthese antennaeare lostintumor the environment surrounding thecells.We’ve antenna –thatsenseandreceive signalsfrom organellesare –similarto multisensory acell ciliumintumorbiology.primary cilia Primary We continueinvestigating therole ofthe maytherapeutic interventions beenvisioned. By understandingthesemechanisms,potential normal celltransforminginto acancerous one. the basicbiologicalprocesses involved witha Research” sectionfocusesonunderstanding The “CancerCellBiologyandTranslational Summary Sergio Gradilone,Ph.D. Cancer Cell Biology and Translational Research SECTION PROFESSOR LEADER / ASSOCIATE to disassembly by amechanismdepen- ciliary process involved inprotein degradation,are linked that degradesorganelles, andubiquitination,a pose here thatautophagy, aphysiologicalprocess the pathogenesisandprogression ofCCA. We pro- pathologic process recently discovered by usin ofcholangiocytedeciliation,a the importance ment. Ourcurrent overall objective isto explore CCA anddevelop newtherapiesforitstreat- goals are to understandthepathogenesisof develop bettertherapies.Thus,ourlong-term regulating diseaseinitiationandprogression to it isimperative to identifythecellularnetworks patic CCA have increased by 165%.Therefore, in thelast4decades,incidenceratesofintrahe- CCA are diagnosedintheUSAeachyear, and, Importantly, more than2,500newcasesof cy withfeatures tractdifferentiation. ofbiliary Cholangiocarcinoma (CCA) isalethalmalignan- Project 1 Loss 1 -MechanismsofCiliary of primary ciliaintegrity.of primary new therapeuticstrategiesbasedontherescue which may contributeto thedevelopment of malignant cellsto amore normal phenotype, ciliaintumorcellsandbringbackthe primary we are nowableto inducetherestoration of as wegainknowledgeonthesemechanisms, consequences ofsuchaloss.Furthermore, and provide the foundation for anti-cancer therapies based on controlling the proliferation and migration of malignant cells, cells, malignant of proliferation migration controlling and the information on fundamental, ciliary-dependent mechanisms the rescue of primary cilia functions, i.eCiliotherapy.” “Our research uncovering is novel and generalizable If you are attaching components byautophagy. the resorption ofciliaandthedegradation oftheciliary expressed HDAC6 andincreased inCCA autophagy induces Figure 1.Ciliophagymodel.Theorchestrated workofover-

the foundation for a potential clinical trial. the foundationforapotentialclinicaltrial. autophagy inhibitioninvitro andinvivo, laying evaluating theeffects ofcombinedHDAC6 and for useinourresearch. Our experimentsare larial treatment, therefore itisreadily available been extensively usedinhumansasanantima- The autophagy inhibitor hydroxychloroquine has to alessaggressive and more normalphenotype. of ciliaontumorcellsandtransformthemback autophagy, itis possibleto restore theexpression by pharmacologicalinhibitionofHDAC6 and/or ( compartments of itscomponentsto thecellular degradative by stabilityandthetransport regulating ciliary in tumorcellsandinducestheresorption ofcilia dent onHDAC6, whichisaprotein overexpressed ciliary components by autophagy. induces the resorption of cilia CCA in autophagy increased and HDAC6 overexpressed 1. Figure

hc idcs nrae i te ees f AP n atvto o PA Oc atvtd PKA activated Once the chemosensory function of primary cilia. PKA. of activation protrusions in migrating cells. HMC can activate LKB1 v F and phosphorylate to unable cAMP is AKT of Inhibited levels the in phosphorylates and activates LKB1, LKB1 phosphorylates and stabilizes PTEN, leading to AKT inhibition. increases induces which Figure 2. Primary Cilium components Autophagy Primary Primary slide photos orfigures please provide a caption for each: iipay model. Ciliophagy Nucleotides are detected by P2Y11 receptor localized in the primary cilium activating AC5, Cilium Figure 1).We hypothesized that

and the degradation of the of work orchestrated The

Sergio Gradilone HDAC6 TFEB

- ci ta i rqie t rognz te yols and cytoplasm the reorganize to required is that actin

ia a ciliary

- independent mechanism emulating

of LKB1 in both ciliated and deciliated cells in of LKB1inbothciliatedanddeciliatedcells (HMC). We foundthatHMCinducedactivation using thecompoundhesperidinmethylchalcone expression,directly LKB1,independentofciliary migration andinvasion, weattemptedto activate for thenucleotide-mediatedinhibitory effects on dependentmechanism wasrequiredvia aciliary migration andinvasion. Asactivation ofLKB1 induced theoppositeeffects, i.e.increased cholangiocytes andtumorcells,thenucleotides In contrast,innormalexperimentallydeciliated and LKB1-PTEN-AKT dependentmechanism. ciliated cholangiocytesviaaP2Y11receptor inhibited migrationandinvasion innormal dependent chemosensationofthenucleotides presence ofextracellularnucleotides, ciliary- for tumorsuppression. We foundthatinthe ciliaacts asamechanism cholangiocyte primary functionof hypothesis thatthechemosensory information into thecell.Here, wetestedthe environmental signalsand thentransmitthis ciliathatcandetectseveralPrimary kindsof Project 2 Lost 2 -ConsequencesofCiliary Back Row: Seth Richard, DaQingYang, Estanislao Peixoto, Kishor Pant Front Row: Trinity Grey, Sergio Gradilone, Biswas Aalekhya FROM LEFTTO RIGHT: ment ofawidevariety ofhumandiseases. number ofclinicaltrialsforthe potentialtreat- known diseaseandcurrently beingusedina devise novel therapies.Thisviruscausesno were recently identified by usandcouldhelp target-genes inthesecellsthat of important tumor cellsandalsomanipulatetheexpression gene therapy tools forspecificallytargeting CCA cells. Ouroverall objective isto develop new cassettes forspecificallytargeting CCA tumor of theviralcapsidstructures andexpression velop effective vectors through themanipulation cells. Ourproposed studiesare designedto de- virus (AAV), forgeneticmanipulationofbileduct based onahumanvirus,theadeno-associated aimed to develop safe andeffective vectors In collaborationwithDr. George Alslanidi,we Project 3 3 -Newtherapiesandtranslationalstudies therapy forCCA. possibility ofusingHMCasanovel studiesforevaluating the further cells ( functioninCCA chemosensory cilia, itispossibleto emulatethis bypassing theneedforprimary by directly activating LKB1and and invasion, andsuggestthat cilia forthecontrol ofmigration functionofprimary chemosensory ofthe highlight theimportance tumor growth. Thesefindings model, wefoundthatHMCinhibited Furthermore, usinganinvivo CCA of migration andproliferation. vitro, resulting intheinhibition ). These data warrant Figure 2).Thesedata warrant

opment andinsuppressing cancer cell survival. potential inpreventing tumordevel mammary - uptake andaerobic glycolysis has showngreat diabetes. InhibitionofATM-mediated glucose formin isknownto belinked to bothcancerand protein kinaseinresponse to insulinandmet- HDAC6 activity. SignaltransductionoftheATM function inbreast cancercellsby inhibitingthe Dr. Gradiloneisto restore p53tumorsuppressor A collaborative project betweenDr. Yang and including breast, prostate, and pediatriccancer. treatment strategiesforvarious typesofcancer, cancer, whichmay leadto novel diagnosisand suppressor isinvolved in the development of ing howdefective synthesisofthep53tumor damage provides betterunderstandingregard- regulation ofp53inductionfollowingDNA metabolism. Thestudyofthetranslational repair, insulinsignaltransduction,andglucose including cellcycle progression, damage DNA are criticalformultiplephysiological processes, proteins, p53andATM,of twoimportant which with Dr. Da-QingYang includetheinvestigation Other studiesintheSectioncollaboration Project 4 sensory function of primary cilia. function ofprimary sensory mechanism emulating thechemo LKB1 viaaciliary-independent migrating cells. HMCcan activate cytoplasm andprotrusions in that isrequired to reorganize the F-actinunable to phosphorylate to AKT inhibition.Inhibited AKT is lates andstabilizes PTEN, leading activates- LKB1,LKB1phosphory activated and PKA phosphorylates cAMP andactivation ofPKA. Once induces increases of inthelevels ciliumactivatingprimary AC5, which by P2Y11receptor localized inthe Figure 2.Nucleotides are detected

-

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 21 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 22 of diagnosis,prevention andtreatment for cancer. defects, wewillprovide insight into newmethods molecular mechanismsunderlying thesecellular regation during mitosis. By understanding the to (mutations) leadto DNA chromosome misseg- progression. Specifically, westudyhowchanges segregations, whichisahallmarkofcancer Mistakes inmitosis lead to uneven chromosome daughter cells-calledcelldivisionormitosis. cells separateduplicatedchromosomes into two for tumorigenesis.We studytheprocess where Our workseeksto understandthecellularbasis Summary Edward H.Ph.D. Hinchcliffe, Cellular Dynamics SECTION LEADER / PROFESSOR Cultured cells showing positionofcentrosome (arrows) exclusively atperi-centromeres, whichare normal mitosis H3.3Ser31isphosphorylated of thehistone variant H3.3atSer31.During anaphase viathedifferential phosphorylation position oflaggingchromosomes during back mechanismthatmonitors therelative Recently wehave identifiedaconserved feed- are notknown. molecular mechanismsunderlyingthistrigger gers cellcycle arrest intheensuingG1.The triggers ap53-dependantfailsafe thattrig- because chromosome missegregation also proliferation ofthesecellsisnormallyblocked, anaphase generatesaneuploidcells,butthe chromosomeInadvertent missegregation in Chromosome missegregation: “We focus on the role of mitotic mechanisms in

the generation of human disease.” somes that lack BubR1 labeling. These cells somes thatlackBubR1labeling.Thesecells the presence ofoneormore misalignedchromo- undergo themetaphase-anaphasetransitionin spindle microtubules withcold.These cells chromosomes by transientlydepolymerizing induced non-transformedcellsto missegregate inanaphase. Werapidly dephosphorylated global phosphorylation of H3.3 Ser31 in both ofH3.3Ser31inboth global phosphorylation ylation alongindividualchromosomes initiates Surprisingly, duringtelophaseSer31phosphor- chromosomes assembleinto amicronucleus. along theirarmsthatpersistsinto G1asthese have H3.3Ser31(pS31) hyper-phosphorylated isolated chromosomes (e.g. lagginginanaphase) same celllive andfixed imaging revealed that damage.After re-warming,lack DNA correlative transit mitosis withrelatively normal timingand is absentfrom theresulting micronucleus. sient; by nuclear envelope reformation ATRX of ATRX withisolatedchromosomes istran- duringanaphase,the association phorylation H3.3 into nucleosomes.Unlike H3.3 S31phos- binding protein –isknownto loadhistone member oftheSWI/SNF familyofchromatin to isolatedchromosome arms.ATRX –a mimicked by thehyperlocalization ofATRX chromosome missegregation event. pS31is trigger p53activation inresponse to asingle an explanationforwhybothdaughtercells fication stepoftheaneuploidfailsafe, and reforming nuclei,suggestingbothanampli- Edward H.Hinchcliffe

to neoplasticprogression. disrupting theaneuploidyfailsafe contributes in pediatricglioblastomas, suggestingthat and nullmutationsinATRX are bothfound more, driver mutationsinH3.3(flanking Ser31) is normallymonitored andsuppressed.- Further This workprovides insightinto howaneuploidy ATRX recruitment to laggingchromosomes. and dependent uponH3.3S31phosphorylation is mediatedviaanovel signalingmechanism – triggered by chromosome missegregation – nuclei¬. Here weshowthatp53cellcycle arrest chromosomes blocksp53accumulation inG1 or ATRX into anaphasecellscontaininglagging of monospecificantibodiesagainsteitherpS31 bilization inthesubsequentG1.Microinjection pS31 andATRX are required to triggerp53sta- Finally, wedemonstratethatpost-anaphaseH3.3

spindle assembly: The roleofthecentrosomeinmitotic triolar MTOC re-assembled, andpriorto NEB, cellsearlyintheircellcycle, anacen- vertebrate when centrosomes were removed from living cated centrosomes isnotknown. We foundthat amphiaster formationrequires splittingofdupli- fore nuclearenvelope breakdown (NEB).Whether microtubule-organizing center(MTOC) wellbe- formed by thesplittingandseparation ofthe amphiaster (“a staronbothsides”)–thatis pair ofpolarized, astralMT arrays –termedan somatic cellsnormallyassembleaconnected assemble anastralspindles.However, vertebrate self-organize around mitotic chromosomes and mal cells,randomlyorientedmicrotubules (MTs) extracts andexperimentallyderived acentroso- remains controversial.vertebrates In cell-free centrioles duringmitotic spindleassemblyin Alyssa Langfald, CharlesDay, Edward Hinchcliffe, Paiton Schwab FROM LEFTTO RIGHT: these cellsexitedmitosis assingle larity to monastral spindles,and pathway couldnotrestore bipo- chromatin-mediated RAN-GTP sistent monastralspindles.The these entered mitosis withper- to split/separatebefore NEB,and However, ~35%ofaMTOCs failed dividedintwo. these karyoplasts Mitosis proceeded ontimeand needed foramphiasterformation. and theactivityofkinesin-5is recruited to theinterphaseaMTOC, dynactin, andpericentrinare all formed. Cytoplasmic dynein, a functionalamphiastralspindle The role ofcentrosomes/

compromised. of bipolarspindleassemblyishighly centrosome, butinitsabsence,thefidelity formation doesnotabsolutelyrequire the that MTOC separationandamphiaster daughters. Ourdatareveal thenovel finding histone H3.3(red), anti-CENPA(green), andDAPI (blue) Isolated chromosome labeledwithanti-modified

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 23 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 24 metastasis, and adverse effects ofcancer therapy. permeability, angiogenesis, cancerprogression, signal transduction pathways involved invascular oratory alsostudiesmolecularmechanismsand drug resistance inlungcancerpatients.Ourlab- therapeutic targets, andstrategiesto overcome rapidly identifypotentialprognostic indicators, without cleartherapeuticoptions. Ourgoalisto discover novel mechanismsthatregulate cancers models, clinicalsamples,andpatientdatabasesto and biochemical approaches to analyze invivo research program integratesmolecular, genetic, section.Our focusofour“CancerBiology” primary Discovering newways to combatlungcancerisa Summary Luke Hoeppner, Ph.D. Cancer Biology SECTION LEADER / ASSISTANT PROFESSOR

Mr 32000(DARPP-32) anditstruncatedsplice monophosphate-regulated phosphoprotein, expression ofdopamine andcyclic adenosine death worldwide.We demonstratethat elevated Lung canceristheleadingcauseofcancer-related progression to inhibitnon-smallcell lung cancer 1. Triggering thedopaminepathway ( used to data identifynewantigens usingRNA-Seq his development ofScanNeo,abioinformaticstool Hormel Institute colleagueDr. RendongYang on Cancer Research , 2018),andcollaboratingwith treatment ofmetastaticprostate cancer( Bioinformatics, 2019). ing BMI1 isapotentialtherapeutictarget for review: Oncogene),contributingto workshow- (preprint:cell survival BioRxiv,2019;underpeer lung cancergrowth andneuroendocrine tumor DARPP-32 andt-DARPP stimulatesmallcell showing forthefirsttimethat ASCL1-regulated cell migration( lung cancergrowth through IKKα-dependent DARPP-32 isoformspromote non-smallcell past year. Highlightsincludediscovering that progress onnumerous research directions this ects. Together, ourgroup hasmadeexcellent contributionsto multipleresearchportant proj - molecular biologytechniquesandmakingim- scientist whoiscurrently learning avariety of is pleasedto bejoinedby ZhuZhu,avisiting stroke aswellcancer. Ourresearch group treatments forcardiovascular diseaseand research, whichisapplicableto findingnew cializes invascular biologyandangiogenesis our lungcancerdiscoveries. Dr. Wang spe- Dr. Alam isprimarilyfocusedonaccelerating two outstandingpostdoctoral research fellows. Kayum Alam, Ph.D. andLiWang, M.D., Ph.D., Our talentedresearch teamconsistsofSk. , 2018), Communications Biology, 2018), Clinical Clinical

in physiologically normalhuman lung. human smallcell lungcancer tissue,butvirtuallyundetectable DARPP-32 proteins (stained brown) are overexpressed in also showsthatt-DARPP expression iselevated tion of62humanlungadenocarcinoma tissues poor overall Histopathological survival. investiga- t-DARPP isoformexpression isassociatedwith lung adenocarcinoma patients reveals elevated (NF-κB2) signaling.Bioinformaticsanalysis of513 kappa-light-chain-enhancer ofactivated Bcells2 migration through non-canonicalnuclear factor B kinase-α(IKKα) thatpromotes NSCLC cell tion betweenDARPP-32 andinhibitory kappa models. We a novel observe physical interac- cells reduces tumorgrowth invivo inorthotopic human non-smallcelllungcancer(NSCLC) while abrogation ofDARPP-32 expression in variant t-DARPP promote lungtumorgrowth, “Our research team focused is on discovering the molecular basis for new and improved lung lung improved and new for cancer therapies.”cancer Luke Hoeppner

Li Wang, ZhuZhu,Luke Hoeppner, KayumAlam Sk. FROM LEFTTO RIGHT: in SCLC patient-derived tumor tissue, but virtually in SCLC patient-derived tumortissue,butvirtually DARPP-32 andt-DARPP proteins are overexpressed andanti-apoptoticErk-mediated survival signaling. SCLC growth through increased proliferation, Akt/ DARPP-32 anditssplicevariant t-DARPP promote es. We models that demonstrateinorthotopic forprognosticnecessary and therapeuticadvanc- form oflungcancer, andnewmolecularinsightsare Small celllungcancer(SCLC) isthemostaggressive survival growth andneuroendocrinetumorcell 2. DARPP-32 drives small celllungcancer resistance to moleculartargeted therapies. understand howDARPP-32 andt-DARPP promote small celllungcancer. Acurrent area offocusisto lung cancer, specificallyEGFRmutantNSCLC and role ofDARPP-32 isoformsindifferent subtypesof target. We are nowbeginningto investigate the of NSCLC andmay represent anovel therapeutic nostic marker associatedwithincreasing stages that DARPP-32 asanegative isoformsserve prog - with increasing tumor(T) stage.Ourdatasuggest infarct, VEGFpromotes repair ofischemictissue. following cardiovascular orcerebrovascular permeability, edema,andtissuedamage.However, stroke, expression ofVEGFleadsto vascular attack or consequences. For example,inheart cancer, leadingto manypathophysiological vascular permeabilityinischemicdiseasesand Vascularendothelial growth induces factor(VEGF) vascular permeability 3. VEGFactivates STAT3 topromote target for the development of new therapies. target forthedevelopment of newtherapies. nostic indicator forSCLC as apotential andserve DARPP-32 isoformsmay represent anegative prog - nisms ofSCLC oncogenesisthatsuggest demonstrate newregulatory mecha- human SCLC cells.Taken together, we transcriptionally activated by ASCL1 in We showthat DARPP-32 isoformsare achaete-scute homologue1(ASCL1). ulated Notchsignalinggenes,including tumoral t-DARPP expression andupreg- a subsetofSCLC patientswithhigh sequencinganalysisreveals lung. RNA undetectable inphysiologicallynormal Phosphorylation of STAT3Phosphorylation of transcription 3(STAT3). signal transducerandactivator its receptor, VEGFR-2, to activate signaling. VEGFsignalsthrough tissue repair mediated by VEGF ischemic while preserving inhibiting vascular permeability achieve the delicatebalanceof of promising therapiesthat will facilitatethedevelopment induced vascular permeability molecular mechanismsofVEGF- Consequently, understandingthe of permeability inSTAT3 wildtype(WT)vs.KO zebrafish (right). knockout (KO) reduces VEGF-induced permeability (middle).Quantification exit ofred dextran from green labeledzebrafish veins(left). STAT3 VEGF promotes vascular permeability byincreased asevident

afflicted by heart disease, stroke,afflicted by heart orcancer. may translateto improved therapiesforpatients in VEGF-inducedvascular permeability, which our results suggestSTAT3 plays acriticalrole in a mammalianmodelsystem.Taken together, promotes VEGF-inducedvascular permeability Cas9 genomeediting.We alsoconfirmSTAT3 knockout zebrafish generatedusingCRISPR- zebrafish modelinconjugationwithSTAT3 vascular permeabilityby utilizingaVEGF-inducible that STAT3 positively regulates VEGF-mediated STAT3 nuclearlocalization.We demonstrate STAT3 association,STAT3 and phosphorylation, cells (HUVEC) thatVEGFinducesVEGFR-2/ We showin humanumbilicalvein endothelial STAT3 to transcriptionallyactivate target genes. promotes itsnucleartranslocation, enabling National Cancer Institute National Cancer Institute National Institutes of Health Grant Review: Journals: PrecisionNature Oncology Partner Editorial Board: Institutional Research Grant American CancerSociety Funding: Other professionalactivities:

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 25 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 26 mediated forces inHSCactivation. also investigate therole of extracellular matrix- regulation of HSC activation. In addition,we stimulation, and(3) epigeneticmechanismsand enterthenucleusinresponseSMAD2/3 to TGFβ receptors inHSCs,(2) mechanismsby which focus on(1) intracellulartrafficking of TGFβ cytokine thatinducesHSCactivation. Sowe Tumor-derived factor TGFβ isthemostpotent Summary Ningling Kang,Ph.D. Tumor Microenvironment and Metastasis SECTION PROFESSOR LEADER / ASSOCIATE (Wang Y. etal.Hepatology, 2019). published by ahigh-impactjournalHepatology microenvironment. Thesedatahave been HSC activation andtheprometastatic liver p300 isanattractive target forinhibiting acetylation andchromatin remodeling. Thus, promoting genetranscriptionviahistone andTAZfor SMAD2/3 andby epigenetically functioning asacytoplasm-to-nucleus shuttle and canonicalroles forHSCactivation by that p300infactplayed bothnon-canonical studies inthisyear, demonstrated wefurther interrogated withadditional mechanistic inducedby TGFβ1. nuclear transport As andTAZ(PSAKRPK) abolishedSMAD2/3 ing thenuclearlocalizationsignalofp300 andTAZ.of SMAD2/3 Additionally, delet- TGFβ1-stimulated nuclearaccumulation vator p300orinhibitor C646inhibited that knockdown ofthetranscriptioncoacti- of2018,wedescribed In the annualreport represent atherapeutic target for liver metastasis. My research myofibroblasts and the activated-HSC/myofibroblasts in turn The bidirectional interactions between cancer and HSCs thus program, funded by NIHR01grant, focuses on identification activation, which may lead to novel targets to inhibit HSC/ promote cancer implantation and proliferation in the liver. “Cancer invasion of the liver induces activation of hepatic of the molecular and cellular mechanisms governing HSC stellate cells (HSCs),which are liver resident cells, into

cancer interactions and liver metastasis.”

Additionally, sequencing weidentified by RNA anddegradationofTβRII. to lysosomalsorting targeting FAK ormutatingY336to FonTβRII led attyrosine phosphorylation 336.In contrast, plasma membraneofHSCs,anditinducedTβRII bound to TβRII andkept TβRII attheperipheral level, active FAK FAK (phosphorylated atY397) activation ofHSCs.At themolecularandcellular andmyofibroblastic phosphorylation, SMAD suppressed TβRII protein level, TGFβ1-induced that targeting thekinaseactivityofFAK indeed muscle actin,fibronectin, or CTGF. We found sion ofHSCactivation markers, alpha-smooth into myofibroblasts wasassessed by expres- tated by immunoblottingandHSCdifferentiation this hypothesis.TβRII protein level wasquanti - and FAK inhibitor PF-573,228were usedto test promoting HSCactivation. FAKY397F mutant trafficking of TGFβ receptor II (TβRII) thereby adhesion kinase(FAK) may regulate intracellular In addition, wetestedthehypothesisthatfocal Ningling Kang about thisproject iscurrently underpeer-review. lysosome-mediated degradation. A manuscript the plasmamembraneandprotecting TβRII from regulates HSCactivation by promoting TβRII to in a tumorimplantationinvivo model.Thus,FAK the tumor-promoting effects ofHSCsinvitro and cytokines. Functionally, targeting FAK inhibited matrix remodeling proteins, growth factors and tumor-promoting factors, includingextracellular TGFβ1 stimulatedHSC to produce apanelof fluenced by FAK inhibitionandthat through FAK, that thetranscriptsof764TGFβ targets were in- hepatic stellate cells TAZ inTGFβ to activation mediate theirnucleartransport of 2018: Poster Presentation attheLiver Meeting,AASLD, Nov. degradation of TGFβ receptor II hepatic stellatecellsby preventing lysosomaltargeting and Focal adhesionkinasepromotes myofibroblastic activation of Oral Presentation attheLiver Meeting,AASLD, Nov. 2018: Presentations: May 16-17,2019 NCI Program Project (P01) Review, ZCA1 RPRB-F(O1), Grant Review: Other professionalactivities: P300 acetyltransferase and scaffolds withSMAD2/3

Back row: XianghuWang, Yuanguo Wang Front row: QingLi,NinglingKang,DonglianLiu FROM LEFTTO RIGHT:

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 27 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 28 objective willbeachieved by determiningthe factors at various stagesoftranscription. This and theregulation by transcription oftheRNAP ontemplate DNA, polymerase(RNAP) RNA termination phases,thetranslocation ofthe the transitionfrom initiationto elongation and initiation complexes withvarious sigmafactors, We shallstudytheformationoftranscription transcription andtheirregulations inbacteria. of theinitiation,elongationandtermination Our overall goalisto provide astructuralbasis Summary Bin Liu,Ph.D. Transcription and Gene Regulation SECTION LEADER / ASSISTANT PROFESSOR differences inpromoter recognition andopen factors. In order to understandtheunderlying 1.1 Transcription initiation withalternative sigma factors anditsregulation by activators scription initiationwithalternative sigma 1. To elucidate themechanismsoftran- appropriate biochemicalexperiments. and X-ray crystallography, aswellby in theprocesses, usingcryo-electron microscopy substratescaptured atvarious steps DNA/RNA functionally associatedproteins andappropriate structures complexed oftheRNAP with of genes, and amajor mechanism for controlling the Transcription regulated is by various transcription expression of agene to is regulate its transcription. “Transcription the is central step in the expression developmental disorders, diabetes, cardiovascular and mutations of transcription factors, including factors. Many human diseases and disorders are associated with misregulation of transcription cancer, autoimmunity, neurological disorders, resistance mechanisms inbacteria. which are oneofthree evolved antibiotic whose products are multidrugefflux pumps, transcription ofmultidrugresistance genes to theeffector ofxenobiotics and activate the understand howMerR-family membersrespond information from thisstudywouldhelpusto factors (MerR-family proteins). Theobtained factor, FNRprotein, aswellothertranscription that includea boundgeneraltranscription obtain thestructures ofinitiationcomplexes transcription regulation atinitiation,weaim to enrich andadvance ourunderstandingof 1.2 Regulationofinitiationby activators. To factors, includingσ32,σ28, σ24 andσ19. initiation complexes withalternative sigma towe shalltry obtainstructures oftranscription complex formationby alternative sigmafactors, disease, and obesity.”

Bin Liu

structures ofthosecomplexes. We to shalltry assembleanddeterminethe and otherATPases, suchasmfd andUvrD. elongation complexes inassociationwithRapA attempt to obtainstructures oftheRNAP repair,transcription-associated DNA weshall transcription reactivation, terminationand In order to understandhowATPases regulate by ATPases the regulationoftranscriptionelongation 2. To understandthemolecularbasisfor enhances intrinsic termination, we shall also try enhances intrinsictermination,weshallalsotry to understandhowthetranscriptionfactor NusA associated terminationcomplexes. In addition, totry obtainstructures hairpin- oftheRNA by ahyper-translocation mechanism,weshall terminator inducestranscriptiontermination 3.1 In order to understandhowintrinsichairpin factors: NusAandNusG regulation by thegeneral transcription transcription terminationandits 3. To characterize thebasisof this typeoftermination. transcription factor NusG,whichenhances different complexes withorwithoutthe towe shalltry obtainstructures ofthe transcriptto the RNA terminatetranscription, meric helicaseRhobindsto therutsitein 3.2 In order to understandhowthehexa- intrinsic terminationcomplexwithNusA. to assembleand determinethestructure ofthe Wei Shi,BinLiu,Abigail Schammel FROM LEFTTO RIGHT:

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 29 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 30 skin cancer. effective approaches to prevent andtreat actionable moleculartargets fordeveloping cancer development, andto identifynovel genomics studiesto betterunderstandskin We integrateepigenomicsandfunctional regulates skinhomeostasisandcarcinogenesis. between geneticandepigeneticfactors that Research inmylabfocusesonthecrosstalk Summary Liang Liu,Ph.D. Chromatin and Epigenetic GeneRegulation SECTION LEADER / ASSISTANT PROFESSOR

biopsy andtumortissuesforgeneexpression Columbia University MedicalCenterto collectskin laborated withformerdermatologist colleaguesat the clinicalutilityofUVGES panel,I have col- damage forcancerriskassessment.To validate sensitive molecularteststo quantifyskinUV potential becausecurrently there isnp This UVGES panelhassignificantclinical UVtargetconsisting ofconserved genes. gene expression signature (UVGES) panel Additionally, wehave definedanovel UV skin cancerprevention andtreatment. mechanism-driven targeted approaches for sponse asactionabletargets fordeveloping identified master regulators ofskinUV re- in skincells.Bioinformaticsanalysishave duced geneticandepigeneticabnormalities multi-omics studiesto elucidateUV-in- past several years, mylabhasconducted UV promotes skincarcinogenesis. In the critical genesandpathways through which significant gapinourknowledgeofthe on UVandskincancer, there remains a Despite decadesofextensive research prevention andtreatment. biomarker development forcancer UV targetgeneidentificationand UV-induced skincarcinogenesis, Project 1.Molecularbasisof underlying mechanism facilitate will the development of better “Understanding the environmental origin of cancer and its cancer prevention strategies and targeted therapies.” tion andtreatment. risk stratifypatientsfortargeted cancerpreven- that canbeeasilyadoptedinclinicalpracticeto develop a cost-effective biomarker-based test types. Thelongtermgoalofthisproject isto specifically associatedwithhigh-riskskinsub- showing thatasubsetoftheUVGES genesare We have obtainedinteresting results preliminary analysis usingtheNanostringnCounterplatform. regulator ofskinhomeostasisviacontrolling thehypothesisthathairlessisamaster support and hairfolliclecycling. Several linesofevidence co-regulator thatisessentialforskinhomeostasis The hairlessgeneencodesatranscriptional Project 2.Hairlesstransgenicin vivo tumorigenesis. tumorigenesis. and woundhealing,UV-induced and immunity, epidermalstemcells models forstudyingskinhomeostasis Research Interests: • • •

prevention andtreatment Novel moleculartargets forcancer Role ofhairlessinepidermalhomeo- stasis, immunityandcarcinogenesis and cancerpathogenesis. Epigenetic mechanismsindevelopment Liang Liu

a pivotal tumorsuppressor geneinskincarcino - These findingsstrongly suggestthat hairlessis rolesplay incancerdevelopment important (12). have identifiedseveral hairlesstarget genesthat keratosis lesions.Through ChIP-seq studies,we down-regulated inhumanSCCs butnotactinic locus. Moreover, hairlessexpression isfrequently we foundfrequent deletions of thehairlessgene cell carcinomas (SCCs) andothercanertypes, squamous skin human In radiation. UV or duction incidence andburden inresponse to chemicalin- hairless alonecandramaticallyincrease tumor demethylase activity. Mutationalinactivation of hairless isanepigeneticregulator withhistone immune response. We recently that reported proliferation, apoptosis, stemcellfunctionand the expression oftarget genesinvolved incell stem cellactivityandskinwoundhealing. methylation inregulating epidermalhomeostasis, hairless, itstarget genes,andtherole ofhistone findings of to define thedemethylaseactivity genesis. We are followinguptheseimportant Patents: • •

squamous cellcarcinoma subtypes” cation of cutaneousactinickeratosis and ing novel diagnostictools forriskstratifi- “UV biomarker genesubsetsfor develop- International Patent Application sun damageandpredict skincancerrisk” “Next-generation biomarkers to detect International Patent Application

Amanda Hinde,Michael Petersen, LiangLiu,Wootae Ha FROM LEFTTO RIGHT: skin cancerdevelopment andimmuneregulation. new target genesthatare criticallyinvolved in skin homeostasisandfunctionto identify genetic pathways by whichhairless modulates Ultimately, weaimto definethegeneticandepi- signaling inDETC activation andskinimmunity. mune geneactivityandto probe therole ofIL-36 the mechanismby whichhairlessregulates im- immunity. We are studiesto performing elucidate suggesting thathairlessmay alsoregulate skin with upregulation oftheIL-1/IL-36 familygenes, dendritic epidermalγδ Tcells(DETCs) coupled HrΔ/Δ skinledto aprofound accumulationof (HrΔ/Δ) invivo model.Lossofhairlessinthe driven epidermal-specifichairless knockout homeostasis, werecently generatedaK14-Cre To definethe role ofhairlessinskin further 2. 1. Publications: 2019 -American Association forCancer 2012 -NewYork Academy ofSciences 2010 -SocietyofInvestigative Dermatology Memberships: Developmental Biology, inpress and cancerdevelopment. Frontiers in Cell & of IL-36 signalingininflammatory diseases Queen etal.,2019.Function andregulation Carcinogenesis 40:687-694 Their Implications forSkinCarcinogenesis. Regulator GenesofUVResponseand Shen etal.,2019.Identification ofMaster Research

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 31 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 32 innovative fordrugdelivery. nanoparticles lecular-targeted therapiesandthedevelopment of of molecularbasis underlyingresistance to mo- tic linksbetweenobesityand cancer, thedissection and abnormalprotein kinaseactivity, themechanis- have hypermethylation includedthecausesofDNA drugs to thediseasesites.In ourlaboratory, studies tive vehicles to efficientlyand specificallydeliver the novel therapeutic reagents anddeveloping innova- from benchto bedsideby meansofcharacterizing and drugresistance, andto translatethediscoveries and protein kinaseactivityincancerpathogenesis protein N modification,mRNA methylation,histoneof aberrant epigenetics(DNA derstand themolecularmechanismsandroles interests ofourresearchPrimary sectionare to un- Summary Shujun Liu,Ph.D. Cancer Epigenetics and Experimental Therapeutics SECTION PROFESSOR LEADER / ASSOCIATE 6 -Methyladenosine) -Methyladenosine) which critically regulates geneexpression atthe mon epitranscriptomic modification onmRNA, The N TKI resistance isfarfrom complete. the delineationofkey epigeneticevents in in epigenomeconfigurationscancercells. Yet acquired TKI resistance to thedynamicvariations a “drug holiday”. In fact,recent studies have linked resistant reversible phenotypesare partially after is relatively prompt upondrugexposure andthe to explainwhytheappearanceofTKI resistance nilotinib), thesegeneticchanges are insufficient of leukemia resistance to TKIs (i.e., imatinib, are themostextensively studiedmechanisms treatment. While theacquired geneticmutations represent amajor hurdle forsuccessfulleukemia clinic, buttherapid appearanceofTKI resistance Multiple RTK inhibitors (TKIs) have entered the (RTKs), suchasBCR/ABL, c-KIT orFLT3 etc. ly associatedwithhyperactive tyrosine kinases Leukemia isanaggressive malignancyfrequent- The roleofmRNA N therapy leukemia resistancetokinaseinhibitor 6 -methyladenosine (m 6 -Methyladenosine in -Methyladenosine in 6 A) isthemostcom-

geneous FTO-m of leukemia cells.We showedthatthehetero - nature ofm upon exposure to TKIs, theprompt andreversible and reversible features. We hypothesize that post-transcriptional levels anddisplays dynamic the increased FTO-m of targeted kinaseactivities.Onthe otherhand, TKIs andcontinuouslypropagate inthe absence that they canwithstandaninitialonslaughtof to upregulate andproliferation survival genes,so and directly mappedm mia (CML) andacutemyeloid leukemia (AML), models, includingchronic myelogenous leuke- characterized TKI resistance indifferent leukemia TKI-mediated killing.To testthis,wemodeledand on, thushelpingasubpopulationofcellsescape eration/anti-apoptotic factors to berapidlyturned m resistant phenotypes.When theFTO-mediated genes, ultimatelyleadingto theestablishmentof enhance expression ofanti-apoptotic/survival rapidly reprogram theirm RTK cellsfacilitatesa subpopulationofcellsto broadly testedagainst leukemia. However, the pathogenesis, their inhibitors (TKIs) have been hyperactive RTKs cruciallycontribute to leukemia are notfullyunderstood. Further, because aberrant methylation,ahallmark ofleukemia, are largely unclear. Themechanismsunderlying biological consequencesofthis dysregulation frequently dysregulated inleukemia, yet the phosphotyrosine kinaseactivity. RTKs are brane-spanning proteins thatexhibitintrinsic Receptor tyrosine kinases(RTKs) are mem- activators inleukemia Receptor tyrosinekinasesareepigenetic been publishedinatop journal,CellResearch. sensitivityto TKIs. Thesefindingshavepartial macologically inhibited,theresistant cells regain 6 A demethylationiseithergeneticallyorphar- 6 A modification allowsasetofprolif- 6 A axis with the homogeneous A axiswiththehomogeneous 6 A functions by TKIs further A functionsby TKIs further 6 A inthetranscriptomes 6 A methylomeinorder

identify the DNA hypomethylating activities of hypomethylatingactivities of identify theDNA light onleukemia molecular biology. Our data and DNMTs inleukemia pathogenesis, shedding and unravel asignalinginteractionbetweenRTKs strate RTKs asnewtypesofepigeneticregulators hypomethylation.These findings demon- DNA expression resulting inglobalandgenespecific first timedocumentedthat TKIs impair DNMT1 ylation inleukemia cells.Ourstudyhasforthe are modulators ofDNMT1-dependent meth- DNA Our studyprovides thefirst evidence that RTKs ation, TSG re-expression, andleukemia regression. pression ofDNMTs hypomethyl- followedby DNA model and humanpatientswithAML impaired ex- cle. Importantly, nilotinibadministrationinvivo lar apoptosis withoutobvious changesincellcy- of AML cellclonogenicityand promotion ofcellu- cell linesandpatientblasts.Thisledto disruption gene through promoter hypomethylationinAML methylation andtheupregulation ofthep15INK4B DNMT1 expression, thediminutionofglobalDNA nilotinib, resulted inareduction ofSp1-dependent methylation. Treatment withtheRTK inhibitor, expression increased, DNMT expression andDNA Knockdown ofRTKs disrupted,whereas enforced pression inleukemia celllinesandpatientblasts. upregulation ofRTKs paralleledDNMT overex- leukemia growth remain elusive. We foundthat molecular mechanismsby whichTKIs suppress

DNA methyltransferasesDNA (DNMT) isakey hallmark methylationmediatedby dysregulationDNA of factors thatare largely unidentified. Aberrant from an interplay ofgeneticandenvironmental disease progression are unclear, itseemsto result that are responsible forAMLdevelopment and treatment. Although theprecise molecular causes blasts. It isalethaldiseasethat lackseffective swift uncontrolled growth ofimmature myelo- sive hematologic malignancycharacterized by the Acute myeloid leukemia (AML) isahighly aggres- epigenetic targetforcancertherapy The FABP4-DNMT1 loopisa new who relapse from current epigenetictherapy. ized methylationincluding those by aberrantDNA TKIs to benefitpatientsubpopulationscharacter- work provides thepreclinical rationaleforusing patients withoutRTK mutations.Altogether, our might bealternative predictors ofresponses in and suggestthataltered methylationprofile DNA tic efficacyinpatientswithouttarget mutations, mechanistic explanationwhyTKIs showtherapeu- methylation inhibitors. Ourdiscoveries provide a TKIs, thussignificantlyexpandingthepoolofDNA Ning Xiang,HaoLiu,Katie Waller Yanhong Tan, JiuxiaPang, Tao Cheng,ShujunLiu, FROM LEFTTO RIGHT:

management ofcancerous lesions. biomedical applicationsthereby improving the the translationofnanotechnology solutionsto miRs andsmallmoleculecompounds, andfoster of nanosciencewithefficient delivery vehicle for and drugresistance, advance ourunderstanding the molecularbiologyofcancerpathogenesis Overall, our discoveries offer newinsightsinto and invivo. by promoter hypomethylation invitro, DNA exvivo methylation andre-expression ofp15INK4B gene regulation ofDNMT1, decrease ofglobalDNA selective inhibitor BMS309403leadsto down- biology. We showthatFABP4 dysfunction by a FABP4-DNMT1 regulatory feedback loopinAML factor signaling,thuselucidatingacrucial (VEGF) occurs through vascular endothelialgrowth strate thatFABP4 upregulation inAML cells methylation.Heredependent DNA wedemon- AML aggressiveness through enhancedDNMT1- fatty acid-bindingprotein 4(FABP4) promotes previously demonstratedthatupregulation of tion fordrugdevelopment have lagged.We toof AML, target yet efforts DNMT dysregula-

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 33 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 34 for fissionofthe mitochondrial outermembrane dynamin family memberDrp1,whichisrequired of intracellular membranetrafficking events; (ii) potential tumorsuppressor involved inamultitude been implicatedinmitochondrial dynamics: (i) a players withmembrane-remodeling activityhave diseases andcancer( of mitochondrial dynamicscontributesto infectious Our current focusisto determinehowdysregulation apoptosis, autophagy and mitochondrial dynamics. regulate fundamentalcellevents, such as proteins assembleinto large complexes and we are studyinghowmembrane-remodeling andMolecularCellBiology Section In theCryo-EM Summary Anna Sundborger-Lunna, Ph.D. and Molecular Cryo-EM Cell Biology SECTION LEADER / ASSISTANT PROFESSOR Fig. 1).Several molecular of plasma membrane fission (1). recruitment andassembly of dynamin1atsites endophilin isoform, endophilinA1, iscriticalfor Our previous datashowthatneuronal-specific cytochrome candsubsequently, apoptosis. pores intheMOM, leadingto therelease of mitochondria where itisactivated to form apoptotic protein thattrans-locatesto the to intracellularpathogens;and(iii) Bax,apro- critical forautophagy during theinnateresponse an GTPase related to thedynamin superfamily (MOM); (ii) Immunity-RelatedGTPase M(IRGM), Mitofusin, OPA1, andIRGM.Image modifiedfrom original(1) the dynaminsuperfamily oflarge atypical GTPases, Drp1, andapoptosismitophagy are controlled bymembersof membrane-remodeling includingfissionfusion, events, Figure 1.Mitochondrial dynamics.Mitochondrial tubulation are initiated and regulated by BAR proteins.” “Cryo-EM allows to us visualize exactly how critical cellular events, such asmembrane remodeling and

since August of2016. Electron Microscopy facilityandhasbeenhere Hormel Institute recruited himto runtheirpremier State, hecamebackto theMidwestwhen developing core abiologicalcryo-EM atPenn apprentice After 6years inthecraftofcryo-EM. training atTheUniversity ofPittsburgh asan Hershey Pennsylvania andreceived further was atthePenn StateCollegeofMedicinein microscopy andelectron optics.Hisfirstposition nation withaprogram focusedsolelyonelectron time, wasoneoftwoprofessional schoolsinthe College inMadisonWisconsin, whichatthe Facility manager. Heisagraduate ofMadison Bob Ashley istheElectron Microscopy Core Anna Sundborger-Lunna Bob Ashley, Cryo-EM Manager Cryo-EM Bob Ashley, Veer Bhatt, AnnaSundborger-Lunna FROM LEFTTO RIGHT: Current researchprojects: 5) 4) 3) 2) 1) brane fragmentation andxenophagy IRGM controls mitochondrial mem- PROJECT 5:Innateimmunity protein LA2-controled lipolysis brane remodeling controls PNP- PROJECT 4:ABHD5-mediated mem- and celldeath pendent membranepermeabilization membrane remodeling controls Bax-de- PROJECT 3:EndophilinB1-mediated autophagosome formation Golgi membranesremodeling controls PROJECT 2:Coordinated regulation of neuronal celldeath PROJECT 1:Membraneshapecontrols tion ofH0andH1i proximal to thelipidbilayer(grey). density bydocking. Cartoons illustrate thealternate positionsofH0(blue)andH1i (red). Note theorienta - diameter of28.5 nm(top panel) and30.5nm(bottom panel) withatomic modelpositioned into protein of N-terminal mapsofendophilinB1-decorated amphipathic H0.(b)Cryo-EM helix, lipid tubeswithouter modeling(I-TASSER) mapandhomology cryo-EM (bottom panel). Arrows denote putative orientations on lipidtubes. (a)EndophilinB1protein domainorganization (top panel), andatomic modelbased on three-dimensional (3D)reconstructionsFigure 2.Cryo-EM ofendophilinB1helical scaffolds assembled Invited Speakers: Other professionalactivities: 2018 • • •

Wayne StateUniversity, Detroit, MI Center forMolecularMedicineandGenetics 2019 Minnesota StateUniversity, Mankato, MN ofBiologicalSciences Department 2019 SANFORD Health,SiouxFalls, SD ofPediatrics Department

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 35 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 36 marrow derived cells. the molecularsignatures ofepidermisandbone sequencingto use nextgenerationRNA determine from the bonemarrow withtheepidermis.We also of skintumorsto determinetheinteractionofcells quantitative histopathologyperform onsections roles ofbonemarrow cellsinepithelialcancers.We cells. Thesemethodsenableusto determinethe cells from skintumors,andbloodbonemarrow rescence ofepidermalcells, activated cellsorting light microscopy ofcellsandtissues,2)fluo- The principaltechniquesweuseare 1)advanced Summary Rebecca J.Morris,Ph.D. Stem Cells and Cancer SECTION LEADER / PROFESSOR cells canbetracked as they move around thebody adhesion molecule (EpCAM). Additionally, these or to marker acellsurface suchasepithelial cell cytoplasmic filamentscalled of certain keratins can beidentifieddue to theirgeneticexpression respiratory tractsare calledepithelialcells,and or liningspaceslike thegastrointestinal and Cells covering suchastheepidermis surfaces phenotypes andpatternsofgeneexpression. growth involves multiplechanges incellular normal maintenanceoftheskinto neoplastic stages are Theprogression easilyobserved. from results ofalonghistory ofwhichonlythelater Skin cancersasseenintheclinicare actually the carcinogenesis invivo in humansandultra-violetradiation-inducedskin between non-melanomaskincancerdevelopment epidemiological evidence andthetightcorrelation etiology ofskincancer, asdemonstratedby both noma skincancersandisdirectly relevant to the radiation isthemajorknowncauseofnon-mela- the USpopulationisoneinfive. Solarultra-violet lifetime riskfordevelopment ofskincancerin cancers exceed allotherscombined;andthatthe all humancancersoriginateintheskin;thatskin nually. It isestimatedthatone-third to one-halfof new casesare diagnosedintheUnitedStatesan- type ofmalignancy, andmore than onemillion quently inthehumanpopulationthananyother and squamouscellcarcinomas occurmore fre - Non-melanoma skincancerssuchasbasalcell stem cells behave, how they move around the body, and “We visualize how cancer happens by determining how experimental models.

how they develop into tumors.” and colleagues have demonstratedthatsome bone proliferative diseasesofthecolon. Moreover, Tamai circulating epithelialcellsincrease insome benign cancer. Third, Pantel andassociatesshowedthat tumors intheHelicobactermodel ofinvivo gastric derived cellsare recruited to andcontributeto colleagues demonstratedthat somebonemarrow with metastaticdisease.Second,Houghton and cells withcharacteristicsofcancerincreases we knowthattheincidenceofcirculating epithelial have beenassociatedwithepithelial cancers.First, Several attributesofbloodborneepithelialcells characteristics andotherattributesare unknown. cannot bedenied,theirfunctionalandphenotypic althoughtheirpresencepatients. Nevertheless, static cellsinbloodandbonemarrow ofcancer thatseekstobiopsy” measure circulating meta- considered “undesirablebackground” inthe“liquid cytokeratin expression. they For are themost part, their repertoire markers ofsurface andcytoplasmic epithelial cellsare heterogeneous withregard to this dateunknown.Thesebonemarrow derived and differentiative capacitiesofthesecellsare to healthy humansubjects”;however, theproliferative markers inbloodandbonemarrow of“normal, There are several ofcellswithepithelial reports cells to investigate theirstemcellepithelialorigin. use theGFPto visualize, isolate,andculture these This enablesfunctionalstudiesbecausewecan the control ofcytokeratin promoters isavailable. since agreen fluorescent protein (GFP) under Rebecca J.Morris

from thelaboratory ofT.C. Wang that whoreported research uponreading thepaperby Houghton etal., We beganto lay the groundwork forthisproposed ofstemcells? properties chronic woundhealing?Dothey actuallyhave But, beyond carcinogenesis, dothey play arole in cutaneous neoplasmsuponskintumorpromotion. bone marrow caninitiatebenignand malignant healing ulcers.For sure, carcinogen-exposed are recruited to cutaneouspapillomasandnon- a reserve population of progenitors. For sure, they Thus, bonemarrow derived epithelialcellsmightbe epithelial cells. ative anddifferentiative ofthecirculating properties conclusion thatisessentialto determinetheprolifer- takenates). Theseobservations together leadto the of cutaneousneoplasms (Park, Morris,andassoci- rived cellscontributeto bothinitiationandpromotion we have recently demonstratedthatbonemarrow de- in anvivo modelofepidermolysisbullosa.Further, marrow derived cellsare recruited to theepidermis

ed andstratified,contributed to thelesionsalong um where they expressed skinkeratins, andproliferat- bone marrow cellsclustered inthecutaneousepitheli- they occupied25%ormore ofthelesionalarea. The marrow cellsinover 40%ofbenignpapillomaswhere tumors. We detectedclustersoffive ormore bone termine therecruitment ofbonemarrow cellsinskin tation inthecontextofaskincarcinogenesis to de- We usedgender-mismatched bonemarrow transplan- Such informationwouldbeexciting. addressing thishypothesishave beenforthcoming. of therecruited cells?Nodefining functionalstudies swered questionfrom thisworkis:whatisthenature of becomingtumor-initiatingcells.A criticalunan- ogen-exposed bonemarrow contains cellscapable differentiation. We alsodemonstratedthatcarcin- keratins, andstratifiedasinepidermalterminal and inaddition,proliferated, produced epidermal buted significantly to non-melanomaskincancer, demonstrated thatbonemarrow cellsalsocontri- cancer inthevivo Helicobactermodel.We then bone marrow derived cellscontributedto gastric with theprogeny ofthehairfollicle a skintumorpromoter alone. noma were afterexposure observed to papillomas andasquamouscellcarci - posed to acarcinogen, several benign transplant from donorspreviously ex- keratins. Further, afterbonemarrow bone marrow cellsto make epidermal of keratinocytes inducedsomeofthe nocytes andfoundthatthepresence of filter-separatedepidermal kerati- marrow adherent cellsinthepresence experiments where wecultured bone tions. We cellculture alsoperformed stem cells,butasseparatepopula- Rebecca Morris, Stephanie Holtorf, CaitlinLura FROM LEFTTO RIGHT:

and treatment have not escapedour notice. epithelial cancers in generalaswelltheirdiagnosis of ourfindings toward understanding theetiologyof development ofnewdisease models.Theimplications and hematology andshouldprovide motivation for open upanewfieldof research inepithelialbiology experiments outlinedhere have thepotentialto stem/progenitors inculture andinvivo models.The lial cellshave functionalcharacteristicsofepithelial determine whetherthebonemarrow derived epithe- humans thephenotypesexpressed. Second,wewill in healthysubjectsto determine thephenotypesin and quantifybonemarrow derived epithelialcells ogy andepithelialbiology. First,wewilldocument far-reaching consequencesforfieldsof hematol- This research issignificant because itwillhave progenitor cellsforuseinregenerative medicine. skin cancer, andmay provide anewsource of of preventing, diagnosing,ortreating non-melanoma these findingsmay aiddiscovery ofnewmethods that by itselfdoesnotcausecancer. Ultimately, tumors inthepresence ofaskin tumorpromoter cells originatinginthebonemarrow caninitiateskin lesions. We alsoconcludethatcarcinogen-exposed viously unrecognized systemic contributionto these papillomas andnon-healingulcersreflect apre- marrow cellsare recruited to a subsetofcutaneous We conclude thatsurprisinglylarge numbersofbone https://doi.org/10.1038/s41467-018-07688-8. neoplasms. Nature Communications (2018). to development ofchronic cutaneous cells andhairfolliclestemcontribute Morris, R.J. Bonemarrow-derived epithelial Trempus, C.,Gordon, D., Wang, T.C., and K.S., Singh,A., Yang, X.,Londono,D., Singh,A., N., Jin,Guangchun,Asfaha,S.,Patterson, Park H.,Lad,S.,Boland,K,Johnson,K.,Readio, Other professionalactivities:

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 37 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 38 two experiencedpostdoctoral fellows, Florina comparative pathologyandgenetics.We employ in thefieldsofcellsignaling, cancer research continue to collaboratewithworldwideexperts Masonic CancerCenter(MCC), have andwill University ofMinnesotaandamemberthe approaches to eliminate cancer. ofthe As part of developing andimproving existingtherapeutic regulates Tumorigenesis, withtheultimategoal mechanisms by whichoncogenic signaling Our sectionisconcernedwiththemolecular Summary James Robinson,Ph.D. Cell Signaling and Tumorigenesis SECTION LEADER / ASSISTANT PROFESSOR Glioma: tients withthiscancerrarely longerthan survive and isresistant to all conventional therapies.Pa grade ofglioma(most lethal), ishighlyinfiltrative, brain tumor. Glioblastoma (GBM), thehighest than thegovernment. cancer researchers intheUnitedStates,other the largest nonprofit source ofgrantfundingfor $800,000. TheAmerican CancerSocietyis nearly Society Research ScholarGrant worth generously fundedthrough anAmerican Cancer Melanoma: Mayo ClinicinRochesterMinnesotathisfall. anewphaseofhertrainingatthe and starts postdoctoral training attheHormelInstitute intern. Hanahassuccessfullycompletedher Undergraduate Research Experience(SURE) Hanson atechnicianandCaoimheFarrell an Grigore M.D., andHanaYang, Ph.D, andNick resistance to theseinhibitors. Thisworkis validating themechanismsofmelanoma’s to studythisissue.We are determiningand provides anexceptional experimentalsystem model ofmelanomawehave developed that always becomeresistant. Usinganovel invivo tors canbedramatic,themelanomasnearly Although theinitialresponse to theseinhibi- BRAFV600E mutations. anomas thatcarry proved forthetreatment ofadvanced mel- vemurafenib, anddabrafenib, are FDA-ap- remains around 16%.Two therapeuticagents, al rateforpatientswithadvanced Melanoma es inmelanoma research, thefive-year- surviv melanoma inMidweststates. Despiteadvanc- CDC, Minnesotahasthehighestincidenceof gerous formofskincancer. According to the Gliomas are the most common primary Gliomas are the mostcommonprimary Melanoma isthemostdan-

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Colon Cancer: children withthisdevastating disease. to develop newtherapiesto improve for survival the role ofthismutationinthesetumorsorder we seekto bringaboutabetterunderstandingof with theHinchcliffe labattheHormelInstitute, (Figure 1)to studythisdisease.In collaboration Histone H3.3.We are developing ananimalmodel is defined by mutationsinthegeneencoding is<9months.Pediatric%; mediansurvival GBM 1-year of<30%and2-year survival of<10 survival ric cancer. It hasa5-year rateof<1%,a survival stem confers theworstprognosis ofany pediat- trinsic pontineglioma(DIPG), aGBMofthebrain is associatedwithsignificantmorbiditydiffusein- grade ofgliomainchildren Pilocyticastrocytoma ops inthemidlineorpons.While even thelowest distinct from theadultdisease.It typicallydevel- nosed. Pediatric GBMisclinicallyandbiologically 12-14 monthsfrom thetimetumorisdiag- esis andadditionalgrowth signalsormutations ed thatlossofAPC isinsufficient fortumorigen- syndromes. datahas demonstrat- Ourpreliminary and wellunderstood oftheinheritedcoloncancer polyposis (FAP), isoneofthe mostclearlydefined a combinationofboth.Familial adenomatous common exposures amongfamilymembers, or contribution, of CRCthatsuggestsahereditary remaining 25%ofpatients have afamilyhistory no obvious evidence ofaninheriteddisorder. The ed in2015.About 75%ofcasesare sporadicwith 132,770 newcasesand49,700deathsanticipat- cause ofcancerdeathsintheUnitedStateswith and prostate cancer, coloncancertheleading 49,700 deathsanticipatedin2015.After lung in theUnitedStateswith132,770newcasesand colon cancertheleadingcauseofdeaths After lungandprostate cancer, patients withcolon cancer. of novel therapiesandimprove the outcomefor ongoing studieswillcontribute to thedevelopment by theNationalInstitutes ofHealth(NIH) andour sections workonColoncancer hasbeenfunded model isnotsufficientcausetumorformation.Our that heterozygous mutationofAPCinadultvivo block thissignaling.A findingis majorpreliminary be possibleto develop targeted therapeuticsto or pre-empting epithelialLOH ofAPC, itshould ing plays adrivingrole intumorigenesis,following stromal cells.If wecanshowthatstromal signal- additional signalsare likely to arisefrom adjacent polyps withoutadditionalgeneticalterations,these models ofFAP develop amultitudeofintestinal β-Catenin andintestinalpolyposis.Sinceinvivo are alsorequired fornuclearaccumulationof

Hana Yang, CaoimheFarrell Florina Grigore, James Robinson, NickHanson, FROM LEFTTO RIGHT: shows theHA-tagged H3.3K27M(nuclear) expressing cells. neovascularization), andimmunohistochemistry image characteristics (pseudopalisading necrosis, mitotic figures, magnification (200×)H&Eimage reveals high-grade tumor staining showsventral brainstem location oftumor. High Figure 1.Histology usinghemotoxylin andeosin(H&E) H&E K27M K27M H&E H3.3K27M (nuclear) expressing cells. immunohistochemistry image shows the HA-tagged mitotic figures, neovascularization), and tumor characteristics (pseudopalisading necrosis, magnification (200×) H&E image reveals high-grade shows ventral brainstem location of tumor. High Histology using hemotoxylin and eosin (H&E) staining Figure.1

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 39 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 40 targeted therapy or patient prognosis. for fied quicklyand accuratelywhichisimportant constitutional and somaticdiseasescanbe identi- this method,indelscontribute to pathogenesisof reliably detects medium-size andlarge indels.With generation sequencingdata. In particular, ScanIndel (indel) mutationsinhumangenome from next anddeletion del to accurately detectinsertion Briefly, wedeveloped newalgorithmnamedScanIn- University ofMinnesotaMolecularDiagnosticLab. for ourcustomized oncologygenepanelsinthe of clinicalgenomicvariant detectionpipelines Our mostrecent workhas beeninthedevelopment Developing novel algorithmsforindeldetection. Summary SECTION LEADER/ASSISTANT PROFESSOR Rendong Yang, Ph.D. Computational Cancer Genomics

FOXA1 Detected bytransIndel,10mutations BRD4 signalinginprostate cancer progression. study revealed thecrosstalk betweenAR and and BRD4inprostate cancerVCaP cellline.Our studies by analyzingtheChIP-seq dataofAR work focusesonprostate cancereipgenomic expressed prostate cancer. Additionally, ourearly and genomic-independentARsplicingvariants work, weidentifieddiverse genomic-dependent encodes theandrogen receptor. Through this structural rearrangements intheAR gene,which We developed anintegratedpipelineto detect epigenetic regulatorofARinprostatecancer. Detecting generearrangement,splicingand HNF_C DNA binding FH Forkhead_N development of precise diagnostic tools that detect specific genetic FORKHEAD NM_004496 TCGA study (lowerpanel) that were missedbyoriginal ten prostate cancer specimens novel deletions inFOXA1 from Figure 1.TransIndel identified “Identifying specific subtypes of prostate cancer and the distinct 50 HNF3 C-terminaldomain Forkhead N-terminalregion DNA bindingsite[nucleotidebinding] aberrations, allowing doctors to reliably predict apatient’s V82GfsX140 100 pattern of mutations associated with them enhance will 150 200 outcome and prescribe personalized treatment.”

D226N

250

D249_M253delinsV D249V N252_C258del M253K F254V 2

E255_N256del F254_G257delinsC

K264_G283delinsR F266QfsX5 300 G279PfsX34

2 350 Q263Afs*60 R262Sfs*57

or RNA-seq data.TransIndelor RNA-seq exhibitscompetitive or linear alignmentsofsplitreads from DNA-seq and large sized deletionsbasedonthe insertions read aligner andreconstructsa short themid- that parsesthechimericalignmentspredicted by We developed transIndel, asplice-aware algorithm cancer genome 1. Detectingnovel indelsfromprostate different breast cancersubtypes. identify networkmodulesthatcan distinguishing array dataandprotein interactionnetworksto algorithm by integratinggeneexpression micro- biomarkers. We have beendeveloping EgoNet Developing algorithmsfordetectingcancer L379_Q385delinsW 400 UTR_3 MISSENSE INFRAME FRAMESHIFT

A423Dfs*17 Y460X 450 2 X473Mext*22 S472Aext*70 studies. TransIndel enhanced Stand-Up- To-Cancer (SU2C) cancer patientsfrom AACR-PCF and 59metastaticprostate Cancer GenomeAtlas (TCGA) cancer patientsfrom The from prostate 333primary datasets andRNA-seq DNA-seq data. We applied transIndelto synthetic andreal DNA-seq tools onbenchmarksusingboth indeldetection state-of-the-art oversuperior performance eight Rendong Yang

reveal thedynamic interplay betweenlncRNAs and compendia of CRPC-associated lncRNAs tational methodsto achieve thefirstcomplete Our current research isdeveloping novel compu- orapprovedpatient cohorts for clinicalpractice. only a few have beenvalidated inindependent haveciated lncRNAs beenidentified to date,but including PCa.Several PCa-specificorPCa-asso- up- ordownload-regulated invarious cancers, haveMany lncRNAs beenshownto beeither representing anewfocusincancerresearch. as playing essentialroles intumorbiology, polymerase II, have increasingly beenrecognized lysine 4(H3K4me3), andtranscriptionby RNA exons, promoter trimethylationofhistone H3at terized by polyadenylation, splicingofmultiple typically>200bp,commonlycharac- (lncRNAs), longnoncodingRNAs Among ncRNAs, (ncRNAs). transcriptome iscomprisedofnoncodingRNAs genome. Thismeansthemajorityofhuman tein-coding genesonlyaccountforabout2%the (about 75%)isactively transcribed, butpro- accepted thatthevast majorityofhumangenome only asmallfractionofourgenome.Itisnowwell studying protein-coding genes,but they represent much insightinto thebiologyofPCathrough resistant prostate cancer(CRPC). We have gained castration- for aggressive disease,particularly the lackofbiomarkers andeffective treatments cant healthimpact.Clinically, itiscomplicatedwith nosed cancerinmenUnitedStates,withsignifi- Prostate cancer(PCa) isthemostcommonlydiag- prostate cancergenome 2. DelineatinglncRNA landscapein indels ( in prostate cancerby identifyingrecurrent FOXA1 the taxonomy andRNA-level alterations ofDNA- Figure 1).

improve thecomputationalmethodologyto detect therapy response orresistance.aims to Thisstudy detected splicingevent withimmunecheckpoint melanoma to correlation oftheexpression ofour seq from renal cellcarcinoma, lungcancerand We utilize wholeexome sequencingandRNA- in humantranscriptome from data. RNA-seq detect previously missednovel splicingevents computational algorithmwhichcansensitively immunotherapy drugs.We have developed anovel ofthepatientshasresponse toonly part such asskin,lungandkidney cancer. However, to beeffective onanumberofcancertypes Immune checkpointblockadetherapy hasproved immunotherapy 3. Detectingnovel biomarkers forcancer the etiologyofPCa. in oflncRNAs which willhighlighttheimportance and tumorigenesis,progression andmetastasis, Rendong Yang, Wang, Yanan Tingyou Ren, EmmaRector FROM LEFTTO RIGHT:

non-responders ortheeffects intheresponders. underlying theresistance ofimmunotherapy inthe dent alternative splicingevents thatplay arole to identifyalistofcandidategenomicindepen- responders andnon-responder patientsisable splicingevents mutationsandRNA inthe DNA associated phenotypes.Integrative analysisof to determinetheirinvolvement inimmunotherapy- and quantifynovel alternative splicingevents and Bioinformatics. 2019Mar18. data. derived neoantigensusingRNA-Seq LH, Wang TY, Wang L,Alam SK,Hoeppner Publication: DoD Idea Development Award 2018 Award: Other professionalactivities: Yang R.ScanNeo:identifyingindel-

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 41 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 42 reduce day. powerusagewhen there isapeakalert of theEnergy Hero program withtheAustin Utilitiesto help facility runningasefficiently aspossible. We are alsopart continuallymakes improvementsdepartment to keep the needed, alongwithanynew equipment thatarrives. This possible. We workwithnewresearchers to setuplabsas the buildingrunningassafe, efficient, and asbeautiful keep thefacilitiesandresearch runningsmoothly, keeping andnewstaffcomingintowith allthecurrent departments The Maintenance,BuildingsandGrounds teamto work Mark Severtson /Building Systems Manager Building OperationsandMaintenance FY19 Annual Report FY19 Annual Report Not Pictured: Brandon Hoium,KimDowney Nate Britt, DuaneGraff, RandyJohnson MarkSevertson, FROM LEFTTO RIGHT: SUPPORTING DEPARTMENTS include aBecton DickinsonFACS ARIA cell analysis.Other shared instruments researchers to real perform timelive the IncuCyte S3Imager whichallows teins, lipids,andsmallmolecules, and to measure interactions betweenpro- plasmonresonance surface technology include theBiacore T200whichuses C1 confocalsystem.Recentadditions tions andFFPEsamplesaNikon isolate high-puritytissuefrom- cryosec tion microscope whichcanbeusedto a Zeiss Palm Microbeam laserdissec- nal grids.Othermicroscopes include eliminate outoffocuslightwithinter- fluorophore optionsandtheabilityto which allowsforawidevariety of several microscopes, aZeiss Apotome mounting onslides.OurCore also includes allow usersto prepare tissuesamplesfor HistoCore Arcadia embedder. Thesedevices Leica TP1020Tissueprocessor and aLeica previous analyzer. Otheradditionsincludea flexibility andhigherresolution thanour tors offers theFortessa greater fluorophore With more excitation lasersandmore detec- X-20include theBDFortessa flowcytometer. New instrumentsaddedto theCore thisyear that they receive theproper maintenance. in theuseoftheseinstrumentsandensure Hormel Institute. We alsoinstructscientists maintains theshared instruments atthe The Shared Instrument Core operatesand Todd Schuster / Core Facility Manager Instrument CoreFacility

Hormel Institute. Institute. Hormel equipment to assistresearch atThe to employing theseandothercore facility listed above. Ultimately, welookforward addition to thenewlyaddedequipment consists ofamicrotome in andcryostat also available foruse.Histology equipment spectrophotometers, andcentrifugesare instruments, chemiluminescenceimagers, Tek Synergy plate reader, real timeqPCR system forprotein crystallography. A Bio- LC system,andaRigakuX-Ray diffraction mass spectrometer withanEksigent Nano II cellsorter, ABSCIEX 5600Triple TOF Todd Schuster, JoshMonts FROM LEFTTO RIGHT:

form are obtained through loan. interlibrary Library. thatare notavailable Articles inelectronic available forpickupinTheHormelInstitute delivered from theTwin Cities campusandare Americaby collectionsize. Booksarein North Minnesota Twin CitiesLibraries,the15thlargest andresourcesthe services oftheUniversity of electronics. Researchers alsohave accessto chemistry, biology, biophysics,medicine,and books andserials.Thesubjectscovered include volumes ofboundjournalsand2,900volumes of collection consistsofapproximately 10,250 staff research aswellspecial projects. The facultyand and onlinematerialsto support center forTheHormelInstitute. It provides print astheinformationresource serves The library Andy Lucas / Librarian Library the twoentities. as liaisonbetween serving istration departments, works closelywiththeUniversity’s centraladmin- sections.Additionally,and support Administration and humanresource assistanceto ourresearch account management,acquisition,compliance we strive to provide thehighestlevel ofclerical, The administrative teamcontinuesto expandas Ann M. Bode, Ph.D. / Interim Executive Director Administration Back row: JulieGerstner, BeckyEarl,Nyayow Dong Front row: MindaAnderson,Stephanie Blaser, Dr. AnnM.Bode FROM LEFTTO RIGHT:

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 43 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 44 here atTheHormelInstitute. assistance to ensure highqualityresearch hard to provide leadingedgetrainingand level research Theteamworks support. and abilitiesrequired formaintaininghigh help to increase theirspecificknowledge whichwill withintheindustry certified are currently workingtowards becoming tune theirskillsets.Two teammembers coursesto finely seminars, andonlineshort attended nationalmeetings,statewide staff. Thispastyear teammembers tonotch services theinstitute’s investigative Group iscontinuallystrivingto provide top The HormelInstitute’s Research Support Kim Klukas / Supervisor Group Research Support Back row: ChelleJacobson, AnLe Front row: ChrissaCampbell, Kate Viker, KimKlukas FROM LEFTTO RIGHT: network connectivityare resource anextremely important forresearchers instruments, from complexto simpleandlarge to small.Computersand for TheHormelInstitute.Maintenanceincludesawidevariety ofscientific along withcomputer, telecommunication,network,andinternetsupport continuesto Services provideResearch Support instrumentmaintenance Jeffrey McDonald / RSS Manager Services Research Support of Research Technology. Hormel Institute’s International Center our supercomputer ofThe room, part away simulatingprotein moleculesin Life-sciences 42)hasbeencalculating CAL42 (Computational Analysis of needs keep usbusy. TheLinuxcluster load. Asalways, thenetworksecurity ofourwork and a majorportion Theresa Tucker, TimLastine Mike Conway, McDonald, Jeffrey FROM LEFTTO RIGHT: FY19 Annual Report FY19 Annual Report Thank you from oneandallatTheHormelInstitute, University ofMinnesota. new discoveries andincreased funding. to pursueresearch bepossibleandcan leadto thatwouldn’t otherwise and projects innew cancerresearch areas. Donationsallow ourscientists In thepastyear, donationshave fundednewtechnology, 17seedgrants, directly fundsresearch –noneto administrative costs. The HormelFoundation, every pennyofeach donationto TheHormelInstitute Institute University ofMinnesota through donations.Thanksto monetary This year, over onethousandindividualsandbusinessesgave to TheHormel Your difference. indeedmakes animportant faithandsupport theresearchso generously andsupport ofTheHormelInstitute, thankyou. can live longer, healthierlives, uninterruptedby cancer. To allwhocontribute their lives to research knowledgesopeople withthebroad goaloffurthering researcherswith theseexpert from around theworld-they have dedicated be achieved andmore answersaccelerated.We consideritaprivilege to work shine thelightontheirresearch so even more andfindsupport research can meaningful discoveries inthequestto prevent andcontrol cancer, ourgoalis The HormelInstitute, University ofMinnesota.As theInstitute’s scientistsseek Our department’s forthecancerresearch guidingmissionisto gainsupport of DEVELOPMENT AND PUBLIC RELATIONS DIRECTOR OF DEVELOPMENT AND PUBLIC RELATIONS Gail Dennison,M.A.,CFRE Gretchen Ramlo, MichelleHjelmen FROM LEFTTO RIGHT: Kathi Brenna Finley, Gerhart, GailDennison,

formoving research forward THANK YOU Iowa RenewableFuels Association Compeer Financial Absolute Energy LLC Pink PumpkinPatch Foundation Blooming PrairieCancerGroup Judi andDickBergen Joel andBethJohnson Tom and Lori Day Kansas Corn Renewable Fuels Foundation Dick andDianeGerhardt andPat RayGary Austin Bruins Dutchtown Jumpers Lynch Livestock Inc. Karl Potach Foundation Bowling fortheBattle Fishing foraCure Plunging forPink Paint theTown Pink Lyle Area CancerAuction Eagles 5thDistrictCancerTelethon Mayo Clinic Hormel Foods Masonic CancerCenter, University ofMinnesota The HormelFoundation University ofMinnesota

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THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 45 Our goal at The Hormel Institute is to intervene, PARTNERS IN GROWTH prevent and control cancer at its earliest possible detection. You - our donors - provide the support that keeps our research moving forward toward achieving that goal. Annual fundraisers, individuals and families, community groups, sports teams, and corporate donors like Compeer Financial, Absolute Every Energy, and Hormel Foods are all part of how we work together. Thanks to The Hormel Foundation, 100% of every donation funds our innovative, world-recognized cancer research. Thank you for your support of The Hormel Institute - through your support, you are helping create a world Dollar where people live longer, healthier lives.

Our donors make a difference. Nearly 17 innovative research projects are underway that would not be possible without your Furthers donations. The studies may be targeted for specific cancers - such as breast, THE HORMEL INSTITUTE //THE HORMEL INSTITUTE PG 46 OF MINNESOTA UNIVERSITY prostate or Wilms’ Tumor cancers - but //THE HORMEL INSTITUTE PG 47 OF MINNESOTA UNIVERSITY the knowledge gained about the initiation and progression of cancer can impact Answers understanding of many cancers. Thank you for joining our mission with your donations - together we will accelerate answers to cancer so people live longer, healthier lives. Today’s EDUCATION, Tomorrow’s DISCOVERIES

K -12 Scientists from The Hormel Institute participate in area science fairs to promote learning the scientific method and to award “The Hormel Institute OUTSTANDING Science Research Award” to students at various grade levels. Researchers also mentor young students by volunteering their time in the Science Fair Mentoring Project and working with students in the classroom to demonstrate techniques and talk about possible career paths. Every sixth grader in Austin gets an opportunity to tour The Hormel Institute, and as students advance in their studies, taking courses like honors biology, they have additional, increasingly impactful interactions with Institute researchers.

EDUCATION TOMORROW’S SCIENTISTS COMMUNITY RESEARCH-FOCUSED

The Hormel Institute has been part of University of Minnesota since its inception in 1942. Educating students has been and remains an important Our mission is to conduct research and provide education in the biological sciences and part of the community outreach of The Hormel Institute, share our knowledge with the world. The Hormel Institute serves as an education hub University of Minnesota. Our scientists and staff help inspire and center of technical and educational expertise for the benefit of the Austin community, interest in science education throughout leadership in surrounding region and State of Minnesota. Education is a core function and we strive to programs for both individuals and organizations, including: inspire interest in science and prepare people for successful biomedical careers. j Advise/serve on dissertation committee for doctoral students j BICB - graduate training for Biomedical Informatics and POST-DOCs Computational Biology students at UMN-Rochester The Hormel Institute is a hub for postdoctoral j GRAUC (Greater Rochester Advocates for Universities training and nearly every lab has a team that and Colleges board) advocate for education in includes new PhDs. Postdoc is the de facto southern Minnesota next step on the academic MISSIONcareer path after STATEMENT j Austin Aspires COLLEGE earning a doctorate degree (Ph.D.). A postdoc The annual Summer Undergraduate Research Experience (SURE) j Riverland Community College - support “Be Your Best” is a temporary position that allows a PhD to internship program gives college undergraduate students the j Austin Science Fair Mentoring Project - mentor continue his or her training as a researcher and opportunity to work with The Hormel Institute scientists on research students gain necessary skills and experience to prepare projects to expand their knowledge of basic research as well as them for the next steps in their research careers. to learn about equipment and techniques that generally are not available in undergraduate academic programs. THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 50 Hepatology. (2019). K., Liu,D., Guo, L.,Chen,Y., Li,Q., .Kang,N. beta-Stimulated HepaticStellateCells. Nuclear Transport inTransforming Growth Factor plasm-to-Nucleus andTAZ Shuttlefor SMAD2/3 H.I. No.2256 H. Phytomedicine, H., Choi,B.Y., Liu, X.,Zhang,M.,Zhou,S.,.Lee,M. signaling pathway incoloncancer. panchalcone ismediatedby directly targeting theTOPK H.I. No.2255 58. (2019). . Contreras-Galindo, R.BMCMedGenomics, M., Estes,J.Gitlin,S.D., Zahn, J.,Elder, J.T., . syndrome, andHIVinfection . their impactoncutaneousT-cell lymphoma,Sezary endogenous retroviruses inhumanpopulationsand H.I. No.2254 E. Elife, 8.(2019). Vu, N.T., Malinina,L.,Simanshu,D. K.,.Brown, R. pase A2alpha. recognition by theC2-domain of cytosolic phospholi- H.I. No.2253 44, 361-374.(2019). D., Liu,K.,Jin,G.,Yan, M., .Dong,Z.EBioMedicine, man andmousecolorectal cancer. H.I. No.2252 nostics, M., Shang,L.,Du,Q.,Li,Y., Xie,L.,.Cao,Y. Thera- hypermethylation of theRIP3promoter. reprogramming inhibitsnecroptosis through the H.I. No.2251 A. M.,Dong,Z., &Kim,D. J.Phytother Res.(2019). carcinoma cells. duces intrinsicapoptosis inesophagealsquamouscell S6 kinase2inhibitor thatsuppresses growth andin- H.I. No.2250 Syst (Seoul), stem cells. dopamine neurons derived from humanembryonic H.I. No.2249 S., Nie,W., .Dong,Z.Carcinogenesis. (2019). interaction. lung carcinoma growth by inhibitingthePREX2-PTEN H.I. No.2248 Biol Sci, S., Zhang,B.,Zhao,X.,Liu,Y., Liao,C.,.Luo, X.Int J fatty liver disease, obesity and cancer. compounds targeting lipidmetabolisminnonalcoholic H.I. No.2247T The Hormel Institute 9 15(8), 1654-1663. (2019). (9), 2424-2438. (2019). Ryu,J.,Park, B.C.,&Lee,D. H.Anim Cells Yeung, Y. T., Fan, S.,Lu, B.,Yin,S.,Yang, 23(3), 219-227.(2019). Hirano,Y., Gao,Y. G.,Stephenson, D. J., p300 Acetyltransferase IsaCyto- Cell growth inhibitionby 3-deoxysap- Structural variation of centromeric Structural basisof phosphatidylcholine Inhibition of LTA4H by bestatininhu- EBV(LMP1)-induced metabolic Lapachol isanovel ribosomalprotein A proteomic analysisof differentiating CELF2 suppresses non-small cell Zu, X.,Xie,Zhang,Y., Liu, K.,Bode, reatment implicationsof natural 61, 152813.(2018). Kaplan, M. H., Kaminski, Kaplan,M.H.,Kaminski, Zhao, R., Huang, Zhao,R.,Huang, Zhao, S.,Yao, K.,Li,

// JULY 1,2018–JUNE30,2019 Cheng, C., Zhuo, Cheng,C.,Zhuo, Wang, Y., Tu, Shi,F., Zhou,

(1), 12(1),

H.I. No.2263 matics. (2019). L., Alam, S.K., Hoeppner, L.H.,&Yang, R.Bioinfor- data. neoantigens usingRNA-Seq H.I. No.2262 Precis Oncol, T., Patel, S.,Bode,A. M.,Lee,M.H.,&Dong,Z.NPJ tool kitforcancerbiologyandoncology. H.I. No.2261 Z. NPJ Precis Oncol, precision oncology. H.I. No.2260 5348. (2019). H., Bao,W., Yang, Z.,Yu, Y., .Yan, F. SciRep, ed-Multidrug ResistantLeukemia. Overcome MicroRNA Regulatory Network Mediat - H.I. No.2259 Y. Cancer Sci, Q., Tan, Z.,Shi,F., Tang, M.,Xie,L.,Zhao,.Cao, carcinoma through activating fatty acidoxidation. promotes radiationresistance of nasopharyngeal H.I. No.2258 F. AmJCancerRes, S., Li,Y., Lu, J.,Chen,C.,Wang, W., Wang, L.,.Tang, nance through. activating EGFR andp38/MAPK down-regulation promotes colorectal cancermalig- 3 (NRF3) islowexpressed incolorectal cancerandits H.I. No.2257 R. K.MethodsMolBiol , family Members. Intermembrane Transport Illustratedby GLTP Super- H.I. No.2267 Mol Carcinog, Z., Jin,G.,Yao, K.,Liu,F., Chen,H.,.Dong, Z. target for inhibitionthegrowth of osteosarcoma. H.I. No.2266 Res, Song, M.,Bode,A. M.,Dong,Z.,&Lee,M.H.Cancer H.I. No.2265 6240-6252. (2019). Krotova, K.,&Brantly, M.JBiolChem, Oshins, R.,Alli, A. A., Tuna, K.M.,Holliday, L.S., disposal. variant alpha1-antitrypsin reveals anovel exosome-mediated mechanismof Z H.I. No.2264 Cao, Y. IntJCancer, Liao, C.,Quan,J.,Cheng,Zhao,X.,Bode,A. M.,& alpha anditsimplicationincancermetabolism. 79(6), 1019-1031.(2019). 3 110(6), 2050-2062. (2019). 58(6), 1056-1067.(2019). Posttranslational regulation of PGC-1 ScanNeo: identifying indelderived CRISPR/Cas9 - Anevolving biological The PGC-1/ERR networkanditsrole in Multifunctional GoldNanoparticles PGC1alpha/CEBPB/CPT1A axis Nuclear factor-erythroid 2-related factor In Vitro Measurement of Sphingolipid Aurora B kinaseasanovel molecular AKT asaTherapeuticTarget for Cancer. Modulation of calreticulin expression , 8.(2019). Kenoth, R.,Brown, R.E.,&Kamlekar,

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Cancer Res, Li, Y., Chen,C.,Cai,Y., Tan, G.,. .Tang, F. JExpClin promote colorectal cancermalignance . cancer andmediatesp53ubiquitin-degradation to H.I. No.2277 Kim, D. J.MolCarcinog, Liu, F., Zu, X.,Xie,Liu,K.,Chen,H.,Wang, T., . suppresses patient-derived esophagealtumorgrowth . H.I. No.2276 Phytother Res, Wang, X.,Chen,H.,Zu, X.,Ma,F., Liu,K.,.Kim,D. J. by direct targeting of AURKA andRSK2. H.I. No.2275 R. J.NatCommun, Boland, K.,Johnson,Readio,N.,Jin,G.,.Morris, of chronic cutaneousneoplasms. and hairfollicle stemcellscontributeto development H.I. No.2274 Theranostics, Li, Y., Wu, Y., Zhou,S.,Duan,C.,Dong,Z.,.Tang, F. and Promotes Colorectal CancerMalignance . dation through Oxidatingp53Methionine 40and160 H.I. No.2273 Cancer, H., Lei,M.,Chen,L.,Zellmer, L.,He,Y., .Liao,D. J.J Necrosis andStress-Induced Cell Death. Mode Different from Apoptosis, SenescentDeath, isms thatPossess aUniqueProgrammed Cell Death Induced OnesinAnimals,ResembleSemi-New Organ- H.I. No.2272 736-742. (2018). L., Shi,X.,Zhang,H.,.Li,Q.Ann ClinLabSci, Spinal Cord inRats. Injury Anti-Apoptotic Mechanism IsNeuroprotective Against H.I. No.2271 Chem, Kang, N.,Malhi,H.,Shah,V. H.,&Maiers,J.L.JBiol critical for hepatic stellatecellactivation. beta) cross-talk withtheunfoldedprotein response is H.I. No.2270 1-6. (2019). S. P., Han,E.H.,Lee,I. K.,&Chi,Y. I. MutatRes, of hepatocyte nuclearfactor 4alpha. H.I. No.2269 (2019). Li, Z.,Lee,M.,.Kim,D. J.CancerLett, COX1/2 andERK1/2. derived xenograft colontumorgrowth by targeting H.I. No.2268 294(9), 3137-3151. (2019). 9 (24), 4726-4735. (2018). 37(1), 284.(2018). 8 MNAT1 isoverexpressed incolorectal Ethyl gallateasanovel ERK1/2inhibitor Gossypin inhibitsgastriccancergrowth Bone marrow-derived epithelialcells MICAL2 Mediates p53UbiquitinDegra- Spontaneous Cancers,But Not Many 3-Iodothyronamine Actingthrough an Transforming growth factor beta(TGF Dimerization defective MODY mutations 3,3’-Diindolylmethane inhibitspatient- 33(3), 640-650.(2019). (19), 5289-5306.(2018). 9 Tian,X.,Liu,K.,Zu, X.,Ma,F., (1), 5293.(2018). 58(4), 533-543.(2019). Lv, J.,Liao,Tan, W., Yang, Park, H.,Lad,S., Singh,P., Tung, Zhou,S.,Lu, J., Wang, L., Shi, M., Zhou, Shi,M.,Zhou, Liu, Z., Li, C., Liu,Z.,Li,C., , 20-30. 448, 20-30. Lu, J., (6), 48(6), 814,

- Int JBiolSci, Lei, M.,Zellmer, L.,Jia,Q.,Ling,P., .Liao,D. J. Compensatory CellProliferation. of Programmed Cell Death,withorwithouta H.I. No.2279 Acta MolCell Biol Lipids,1864(2), 158-167.(2019). Chalfant, C.E.,&Brown, R.E.BiochimBiophys carcinoma cells. transfer protein (GLTP) inducesnecroptosis incolon H.I. No.2278 behaviors of pancreatic cancer cellsby inducing (2018). Q., Zhou,T., Guo,Y., .Lan,G.Gene, of Bama mini-pig. proteomics inT2DM-susceptible and-tolerant models H.I. No.2287 2 research. H.I. No.2286 1062-1076. (2018). Liu, J.,Pang, J., Zhao, N.,.Liu,S.CellRes, tyrosine kinaseinhibitors. ylome regulates intrinsicand acquired resistance to H.I. No.2285 1582-1598. (2019). S., Richard, S., &Gradilone,S.A. Hepatology, and Tumor Growth . Cilia RegulatesCholangiocyteMigration, Invasion, H.I. No.2284 3686-3694. (2018). Z., Li,Y., Bode,A. M.,&Cao,Y. CancerSci, homeostasis andcelldeath. H.I. No.2283 5567-5576. (2018). Shen, Y., Dou,H.,.Yang, D. Q.CancerMed, signaling pathway. epithelial-mesenchymal transitionviaHedgehog H.I. No.2282 4394. (2018). der Jeught,K.,Fang, Y., .Lu, X.NatCommun, polymeraseII. RNA 17p renders prostate cancervulnerableto inhibitionof H.I. No.2281 (2019). X., Zu, X.,.Kim,D. J.CancerLett, vitro andinvivo. inhibitor thatsuppresses esophagealcancergrowth in H.I. No.2280 , 11.(2018). Bode,A. M.,&Dong,Z.NPJ Precis Oncol, 14(13), 1800-1812. (2018). Evaluating theRemoteControl Upregulation of humanglycolipid iTRAQ andPRM-based quantitative Recent advances inprecision oncology A dynamicN(6)-methyladenosine meth- Function The Chemosensory of Primary Mitochondrial networkstructure Vasohibin 2promotes malignant Heterozygous deletionof chromosome Gossypetin isanovel MKK3 andMKK6 Xie,X.,Liu,K.,F., Chen, H.,Wang, Mishra,S.K.,Stephenson,D. J., Yan, X.,Wu, Y., Zhong,F., Jiang, Zhang,Y., Xue, X.,Zhao,Qin,L., Li,Y., Liu,Y., Xu, H.,Jiang,G.,Van Mansini,A. P., Peixoto, E.,Jin, Yan, F., Al-Kali, A., Zhang,Z., Xie,L.L.,Shi,F., Tan, Dou, X., Chen, L., Dou,X.,Chen,L., , 126-136. 442, 126-136. , 119-127. 675, 119-127. (12), 109(12), (11), 28(11), 7 (4), 69(4), (11), (11),

9

(1), (1), 265-278. (2018). B., .Dickinson,S.E.CancerPrev Res(Phila), Burkett, N.B.,Tahsin, S.,Myrdal, P. B.,Aodah, A., Ho, Tumorigenesis inSKH-1 Mice. Using Topical Resatorvid Blocks Solar UV-Induced Skin H.I. No.2297 Z., &Cao,Y. CancerSci, malignancies. stein-Barr viruslyticreplication for EBV-associated H.I. No.2296 502(3), 389-396.(2018). Ryu, J.,&Lee,D. H.BiochemBiophysResCommun, ulates theSUMOylation andaggregation of Ataxin-1 . H.I. No.2295 Z. Oncogene, Zykova, T. A., Zhu,F., Nadas,J.,Kim,H.G.,.Dong, cancer prevention andtherapy. H.I. No.2294 620. (2018). H., .Dong,Z.CancerPrev Res(Phila), T., Wang, Q.,Fredimoses, M.,Gao, G.,Wang, K.,Chen, Melanomagenesis By Targeting BRAF andPI3K. cones 4-hydroxyderricin andXanthoangelolSuppress H.I. No.2293 Mol TherMethodsClinDev, Y., Rodriguez,J.,Mazur, M.,Birket, S.E.,.Suk,J. Gene Therapy . Capable ofPenetrating theMucus Barrier to Inhaled H.I. No.2292 (2018). . Saleem,M.ClinCancerRes, Astone, M.,Ferrari, M.G.,Maqbool,R.,Umbreen, S., in Race-specific Models. Is APotential TherapeuticTarget: HypothesisTested Cancer inCaucasianandAfrican-American Men and H.I. No.2291 Metab, Y., Yan, X.,Yan, F., Sun,Y., Zeng, J.,.Li,B.Cell Breast/Mammary Tumor Development. Protein IsaNewLinkUnderlyingObesity-Associated H.I. No.2290 Cao, Y. Theranostics, cancer. effect andtumorgrowth through HIF1alpha inlung H.I. No.2289 57(12), 1763-1779.(2018). Liu, Z.,Xie,H.,Jiang,Y., .Tang, F. MolCarcinog, carcinomaryngeal metastasis. through innasopha- upregulating miR-149 participates H.I. No.2288 Li,J.,He,Y., Tan, Z.,Lu, J.,Li,L.,Song,X.,. 28(5), 689-705.e685. (2018). Li,H.,Hu,J.,Luo, X.,Bode,A. M.,Dong, 37(42), 5633-5647.(2018). Duncan, G. A., Kim, N., Colon-Cortes, Duncan,G.A., Kim,N.,Colon-Cortes, Pharmacological TLR4 Antagonism Pharmacological TLR4Antagonism Therapies basedontargeting Ep- Dual-specificity phosphatase18mod- Targeting PRPK andTOPK forskin The Ashitaba(Angelicakeiskei) Chal- An Adeno-AssociatedViralVector BMI1 Drives of Metastasis Prostate Circulating AdiposeFatty AcidBinding Wild-type IDH2promotes theWarburg Dinitrosopiperazine-decreased PKP3 8 (15), 4050-4061. (2018). Ganaie,A. A., Beigh,F. H., 109(7), 2101-2108.(2018). 9 Blohm-Mangone, K., Blohm-Mangone,K., Li,Y., Ju,K.,Wang, W., , 296-304.(2018). Roh, E., Lee, M. H., Roh,E.,Lee,M.H., (24), 6421-6432. 24(24), 6421-6432. Hao, J., Zhang, Hao,J.,Zhang, 11(10), 607- Zhang, Zhang, (5), 11(5), 138(9), 1925-1934. (2018). Y. W., .Li,B.JournalofInvestigative Dermatology, Zhang, Y. W., Hao,J.Q.,Zeng, J.,Li,Q.,Rao,E.Y., Sun, Induced IFN/p53/SOX2 Pathway inKeratinocytes. Induced SkinTumorigenesis by RegulationofTPA- H.I. No.2300 16723. (2018). , L. JournalofBiologicalChemistry Samygina, V. R.,Zhai,X.H.,Mishra,S.K.,.Malinina, family. golipid recognition by theglycolipid transfer protein adaptor protein 2yieldmechanisticinsightsinto sphin- H.I. No.2299 3061-+. (2019). , Suciu, R.,.Buckanovich, R.J.CellReports I., Grimley, E.,Yang, K.,Hong,L.D., Vinogradova, E.V., Necroptosis inOvarian CancerStem-like Cells. H.I. No.2298 Ochoa-Lizarralde,B.,Gao,Y. G.,Popov, A. N., Epidermal FABP Prevents Chemical- Structural analyses of 4-phosphate Structural analysesof 4-phosphate A Pan-ALDH1A Inhibitor Induces 293(43), 16709- Chefetz, (11), 26(11),

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 51 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 52 in humanABCB1/p-glycoprotein” andinhibition “Molecular insightsinto drugtransport Zurich ETH Scientific Coordinator 2 Amer Alam, PhD August 28,2018 “Melanoma Immunotherapy” Mayo Clinic Professor ofOncology Professor ofMedicine Svetomir N.Markovic, MD, PhD August 17,2018 “Modulating ImmuneFunction inLymphoma” Mayo Clinic Professor ofMedicine Stephen M.Ansell, MD, PhD August 16,2018 replication” the impactofcocaineonHIV geneexpression and “HIV latency, themajorhurdle inHIVeradication;and The George Washington University Tropical Medicine ofMicrobiology,Department Immunology, and ofMedicine Department Assistant Professor 2 Mudit Tyagi, PhD August 14,2018 Normal andDisease Hematopoiesis” “Bone Marrow Niche SignalingintheRegulationof Loyola University Chicago ofPathology Department Associate Professor 2 Jiwang Zhang,MD, PhD August 7,2018 Agents for Brain Development andDiseases” “Development of RetinoidBased andPharmacological Icahn School of MedicineatMountSinai Sciences ofMedicineand Pharmacological Departments Associate Professor 2 Bhaskar Das,PhD July 24,2018 “Regulating Apoptosis by DeubiquitinaseUSP35” University ofColoradoSchoolMedicine andMolecularGenetics ofBiochemistry Department Associate Professor 2 Chang-Wei Liu,PhD July 17,2018 “Novel Regulators of Growth Control” Rutgers University Waksman Institute ofMicrobiology Postdoctoral Associate 2 Jyoti R.Misra,PhD July 10,2018 The Hormel Institute nd nd nd nd nd nd Interview Interview Interview Interview Interview Interview Interview

// JULY 1,2018–JUNE30,2019

in Fibrosis andCancer” “Instability ofCentromere Repeats andRetroelements University ofMichigan Division ofInfectious Diseases ofInternal Medicine Department Research Assistant Professor 2 Rafael Contreras, PhD October 16, 2018 LINC complexes inhealthanddisease” “Building andbreaking nucleo-cytoskeletal bridges: University ofMinnesota Genetics, CellBiology, andDevelopment Assistant Professor G.W. GantLuxton, PhD October 11,2018 inIschemicBrain”“Nrf2 University ofPittsburgh ofNeurology Department Assistant Professor “Interplay ofGeneticandEpigeneticFactors in Columbia University ofDermatology Department Assistant Professor 2 Liang Liu,PhD September 25,2018 anddrugdiscovery” metabolismindisease “RNA University ofIllinois,Chicago ofPharmacology Department Assistant Professor 2 Zain Paroo, PhD September 11,2018 “How docellsunlockthegateway to apoptosis?” University ofNebraskaMedicalCenter Eppley Institute forCancerResearch Associate Professor 2 Feng Zhang,PhD October 9,2018 “English Pronunciation forAcademics” University ofMinnesota Education Program Specialist Elena Stetsenko October 4,2018 “English Pronunciation forAcademics” University ofMinnesota Education Program Specialist Colleen Meyers October 4,2018 UV-induced SkinTumorigenesis” 2 Xu Lou,PhD September 4,2018 recognition andinitialmyelin sheathformation” “The CNSmyelin landscape: mechanismsof axon Winona StateUniversity Assistant Professor Jake Hines,PhD August 30,2018 nd nd nd nd nd Interview Interview Interview Interview Interview Interview

SEMINARS

“TBD” Case Western University Reserve ofPharmacology Department Assistant Professor Jason Mears,PhD December 20,2018 “TBD” University ofMinnesota ofSurgery Department Division ofBasic&Translational Research Professor Masato Yamamoto, MD, PhD December 13,2018 “A Research Seminar&Spore Grants” Mayo Clinic ofOncology Department Division ofOncologyResearch Professor ofPharmacology Professor ofMedicine Scott H.Kaufmann,MD, PhD December 6,2018 “Updates from Office of Technology Commercialization” University ofMinnesota Office of Technology Commercialization Venture CenterProgram Manager MacCarthy Mary November 16,2018 “Updates from Office of Technology Commercialization” University ofMinnesota Office of Technology Commercialization Senior Technology Manager Portfolio Karen Kaehler November 16,2018 “Getting to Know Your OwnCulture” University ofMinnesota GPS GlpbalPrograms &Strategy Education Program Specialist Thorunn Bjarnadottir November 8,2018 “FGFR4 Promotes Cholangiocarcinoma Progression” University ofNebraskaMedicalCenter &MolecularBiology ofBiochemistry Department Associate Professor Justin Mott,MD, PhD October 25,2018 mechanisms of genomestability” “Finding thebalance within:Integratingresearch on University ofGeorgia Assistant Research Scientist 2 Wioletta Czaja, PhD October 23,2018 cer Metastasis to Transform CancerPatient Outcomes” “Translating InsightsGainedfrom Intravital Imagingof Can- Mayo Clinic ofUrology Department Senior Associate ConsultantII 2 Hon S.Leong,Msc,PhD October 19,2018 nd nd Interview Interview Interview

“BRCA1-BARD1 promotes endresection of DNA Yale University SchoolofMedicine Dept. ofMolecularBiophysics&Biochemistry Associate Research Scientist James M.Daley, PhD June 4,2019 “Alternative Careers after PhD” UMN GenomicsCenter Director Kenneth Beckman,PhD May 9,2019 andhumanhealth”“Gut bacterialmetabolism University ofWisconsin–Madison Assistant Professor ofBacteriology Federico Rey, PhD May 2,2019 oncoproteins inliver cancer” “Deciphering theanti-oncogenic effects of classical UC SanDiego Professor ofPathology &Biology Gen-Sheng Feng, PhD April 25,2019 “Bioinformatics Core” Mayo Clinic Professor ofBiomedicalInformatics Jean-Pierre A. Kocher, PhD April 18,2019 “Tissue engineeringandregenerative medicine” Mayo Clinic ofCardiovascularDepartment Medicine Professor ofMedicine Amir Lerman, MD February 21,2019 Chemotherapy Response” Correlation Datawith of SingleCell RNA-Seq University ofMinnesota Women’s Health(OBGYN) ofObstetrics,Gynecologyand Department Assistant Professor Tim Starr, PhD 10,2019 January A ‘complex’ way to regulate nucleotide metabolism” Optimizing theimmune systemto fight disease; and Stony Brook University &CellBiology Dept. ofBiochemistry Dept. ofChemistry Assistant Professor Jarrod B.French, PhD June 25,2019 ultraviolet radiationinduced immunesuppression” “Senescence associatedsecretory phenotype in University ofAlabama,Birmingham ofDermatology Department Professor Hui Xu, PhD June 6,2019 double-strand breaks”

Income fromGrants,ContractsandDevelopment The Hormel Institute Foundation forWomen’s Cancer American CancerSociety National InstituteofHealth Pennsylvania StateUniversity Pardee Foundation Ovarian CenterResearchFund Life ScienceResearchFoundation National CancerInstitute National InstitutesofHealth Prostate Cancer Foundation Institutional Research Grant(L.Hoeppner) Determination &validation ofresistance mechanismsinmelanoma Targeting eIF4A1-dependent HK2translation axisforprevention of CiliumasaTumorThe CholangiocytePrimary Suppressor Prevention ofsolarUV-induced SkinCancer by Targeting LTZ4H Translational development studies ofanovel combinationtherapy Prevention ofprostate carcinogenesis by next-generationselenium Necroptosis: molecular andmetabolicaspects(I. Chefetz-Menaker) Chemoprevention ofColonCancerby Targeting theWnt/beta Drugs Inducing Necroptotic forhighgrade CellDeathasaNewStartegy Identification andcharacterization ofcancerstemcellsin ovarian cancer Necroptosis inovarian cancercells with gainoffunctionp53mutations Mechanism ofhigh-efficienytransductionhepatocytes by Targeting HighFat hypermethylationforAML Diet-Driven DNA Hepatic StellateCellRegulationofMetastaticGrowth inthe Developing NewOrnithineDecarboxylase Inhibitors to Prevent Delineating coding andregulatory indelsinprostate cancer(R. Yang) ovarian cancerChefetz-Menaker) (I. (I. Chefetz-Menaker) (I. Chefetz-Menaker) (J. Robinson) optimized AAV vectors (G. Aslanidi) castrationresistant prostate cancer(Y. Deng) Organelle (S. Gradilone) chemoprevention (S. Liu) (Z. Dong) for castration-resistant prostate cancer(Y.Deng) (Y. Deng) Catenin Pathway (Z. Dong) Liver (N. Kang) Skin Cancer(Z. Dong)

// JULY 1,2018–JUNE30, 2019

$240,760 $240,760 $213,750 $213,750 $266,754 $266,754 $222,552 $222,552 $80,000 $80,000 $228,750 $228,750 $156,157 $150,000 $86,744 $86,744 $30,000 $30,000 $50,000 $46,374 $54,534 $93,375 $93,375 $75,000 $54,534 $54,534 $12,936 $12,936 INCOME Bob Allison Ataxia ResearchCenter Mayo ClinicRochester PhRMA Foundation Prevent CancerFoundation University ofMinnesotaFoundation Total Other Resources ofDefense Department University ofSouthFlorida/NIH University ofMinnesotaMedicinalChemistry/NIH University ofFlorida/NIH Function ofATM inNeuronal inResponseto Survival Growth Mayo Clinic-HormelInstitute collaboration(S. Liu) Accurate detectionofstructrualvariation from sequencing DNA A novel UVsignature forassessingskinUVdamageandcancerrisk Discovery ofa novel beta-catenininhibitor thatshowspotent Fundraising/Development Indirect Cost Return University ofMinnesota The HormelFoundation Cellular mechanismsunderlyingpediatricglioblastoma: The Functional Interaction inSepsis RoleofthecPLA2alpha/C1P The Functional Interaction inSepsis RoleofthecPLA2alpha/C1P Smoking-induced epigeneticchangesinthelung:RoleofDNA Mechanism ofhigh-efficiencytransductionhepatocytes by Factor Signaling(D. Yang) of circulatinf tumorcells(R. Yang) instability by abolishing Ser31 phosphorylation (T. instability by abolishingSer31phosphorylation Hinchliffe) Heterozygous mutationsinhistone H3.3inducechromosome (L. Liu) therapeutic effects againstcolonecancer(S. Shin) Resolution (R. Brown) Resolution (E. Hinchcliffe) demethylation (S. Liu) optimized AAV vectors (G. Aslanidi)

$9,893,939 $9,893,939 $4,538,500 $4,538,500 $1,123,822 $1,123,822 $400,000 $400,000 $123,047 $123,047 $62,000 $166,667 $166,667 $887,753 $887,753 $142,633 $142,633 $15,000 $15,000 $118,186 $118,186 $50,000 $50,000 $43,000 $43,000 $63,158 $63,158 $97,953 $97,953

THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 53 THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 54 The Hormel Institute Austin, MN Hormel Foods Corporation President andCEO Chairman oftheBoard, Jim Snee Minneapolis, MN University ofMinnesota Vice President forResearch, Chris Cramer, Ph.D. Rochester, MN Mayo Clinic Executive Dean forResearch, J.Gores,Gregory M.D. Austin, MN The HormelFoundation Chair, Jeffrey M.Ettinger Rochester, MN Mayo ClinicCancerCenter Director, B.Diasio,M.D.Robert St. Paul, MN University ofMinnesota Natural Resource Sciences, Dean, CollegeofFood, Agriculturaland Brian Buhr, Ph.D. Austin, MN University ofMinnesota The HormelInstitute Interim Executive Director, Ann M.Bode,Ph.D. Board Advisory The HormelInstitute

(effective until11/14/2018) Austin Area Foundation Executive Director Jeffrey A. Baldus YMCA ofAustin Executive Director Diane B.Baker Campus Riverland CommunityCollege–Austin President Dr. Adenuga O. Atewologun (effective until1/31/2019) Salvation Army Commanding Officer David D. Amick (effective asof11/14/2018) Parenting Resource Center, Inc. Executive Director Gema Alvarado-Guerrero Adams, Rizzi&SweenP.A. Attorney Secretary, Steve T. Rizzi,Jr. Hormel Foods Corporation Treasurer former VicePresident ofFinanceand Treasurer, RolandG.Gentzler City ofAustin former Mayor Vice Chair, BonnieB.Rietz (effective until8/15/2018) Hormel Foods Corporation Foods Group former President ofRefrigerated Chair, J.Ray Gary (effective asof8/15/2018) Hormel Foods Corporation President andCEO Former ChairmanoftheBoard, Chair, Jeffrey M.Ettinger Board ofDirectors The HormelFoundation

ADVISORY BOARD

(effective until3/19/2019) YMCA Austin Executive Director Tedd M.Maxfield (effective asof6/30/2019) United Way ofMowerCounty, Inc. Interim Executive Director Molly S.Lanke Austin PublicSchools Superintendent David M.Krenz Inc. Ameriprise FinancialServices, Financial Planner Certified Randall J.Kramer (effective asof8/15/2018) Baudler, Maus,Forman &King,LLP Attorney Michelle M.King Hovey, LLP Hoversten, Johnson,Beckmann& Attorney andPartner Craig W. Johnson (effective until6/30/2019) University ofMinnesota The HormelInstitute, Executive Director Dr. ZigangDong City ofAustin Finance Director Thomas J.Dankert Lea and Albert Mayo ClinicHealthSystem-Austin President andCEO Dr. MarkR.Ciota (effective asof6/30/2019) University ofMinnesota The HormelInstitute, Interim Executive Director Dr. Ann M.Bode

The Hormel Institute The HormelInstitute (effective asof1/31/2019) The Salvation Army ofAustin Commanding Officer Jeffrey L.Strickler (effective asof7/14/2018) Hormel Foods Corporation Chairman oftheBoard, President andCEO James P. Snee Hormel Foods Corporation former VicePresident ofEngineering J.PfeilLarry Cedar Valley Inc. Services, Executive Director Richard R.Pavek Chinese Academy ofEngineering Shanghai, China Institute/Hospital Eastern Hepatobiliary Surgery Hong Yang Wang, Ph.D. Association ofAmericanPhysicians San Diego,CA Moores CancerCenter University ofCalifornia,SanDiego Scott Lippman,M.D. D.E. RogersMedalinHealthPolicy New York, NY Columbia University Christina Hoven, Ph.D. National Academy ofSciences Columbus, OH The OhioStateUniversity Carlo Croce, M.D. Austin, MN University ofMinnesota The HormelInstitute, Interim Executive Director Ann M.Bode,Ph.D. Board Scientific Advisory

The Hormel Institute Zhenbo Song Visiting Scholar Yu Wang Researcher 1 Puja Singh Peng Li Hormel Fellow Yibin Deng,Professor Cell Death&CancerGenetics Imran Khan Anmbreen Jamroze Naresh Golla Mikhail Chesnokov Hormel Fellow Ilana Chefetz, Assistant Professor Cancer StemCells&Necroptosis Ning Xiang Yanhong Tan Xiaochang Liu Hao Liu Tao Cheng Visiting Scholar Jiuxia Pang Researcher 1 Shujun Liu, Associate Professor Experimental Therapeutics Cancer Epigenetics& Zhen Wang Yixin Wang Jianxin Tao Visiting Scholar Xiufeng Jiang Visiting Associate Professor Seth Richard Aalekhya Biswas Researcher 2 Estanislao Peixoto Postdoctoral Associate Kishor Pant Hormel Fellow Daqing Yang Research Assistant Professor Sergio Gradilone, AssociateProfessor Translational Research Cancer CellBiology& Zhu Visiting Scholar Li Wang Sk Kayum Alam Hormel Fellow Luke Hoeppner, Assistant Professor Cancer Biology

// JULY 1,2018–JUNE30, 2019 Jinhua Wang Xiaoyu Chang Summer Term RA Junsheng Zhu Yi Yang Yifei Xie Yanan Jiang Visiting Scholar Tara Adams TechnicianPrincipal Laboratory Teri Johnson Researcher 1 Tianshun Zhang Quishi (ChoCho)Wang Joohyun Ryu Moeez GhaniRathore Raja Dey Hanyong Chen Faisal Aziz Researcher 5 Hisae Yoshitomi Seung HoShin Azeem Saeed Souren Paul Xinli Ma Jian Li Le DeVittoHumberto Abhijit Chakraborty Ali Calderon Hormel Fellow Eunmiri Roh Kanamata Reddy Wei-Ya Ma Research Assistant Professor Ke Yao Research Associate Professor Zigang Dong,Professor Cellular &MolecularBiology Caoimhe Farrell Visiting Scholar Nick Hanson Researcher 1 Hana Yang Florina Grigore Hormel Fellow James Robinson,Assistant Professor Cell Signaling&Tumorigenesis

Noah Johnson Temporary Researcher Karina Krotova Research Assistant Professor George Aslanidi, Associate Professor Cancer Vaccine Molecular Bioengineering& Lucy Malinina Visiting ResearchAssociate Professor Yong-Guang Gao Research Assistant Professor Rick Brown, Professor Membrane Biochemistry Rafael Contreras, Assistant Professor Chromosome Biology Genome Instability& Wioletta Czaja, Assistant Professor DNA Repair&Genome Stability Qi Hu Maria Victoria Botuyan Visiting Scholar Veer Bhat Postdoctoral Associate Anna Sundborger-Lunna, Assistant Professor &MolecularCellBiology Cryo-EM Yanan Ren Visiting Biostatistician Tingyou Wang Hormel Fellow Rendong Yang, Assistant Professor Computational CancerGenomics Chathumadavi Ediriweera Visiting ResearchScholar Amanda Hinde Researcher 1 Wootae Ha Hormel Fellow Liang Liu, Assistant Professor Regulation Chromatin &EpigeneticGene Paiton Schwab Temporary Researcher Alyssa Langfald Researcher 3 Charlie Day Researcher 5 Ted Hinchcliffe, Professor Cellular Dynamics FACULTY ANDSTAFF

Brandon Hoium Matt Edwards Kim Downey Duane Graff Nate Britt Randy Johnson Mark Severtson, Building Systems Manager Building Operations&Maintenance Janarjan Bhandari, Manager Cryo-EM MicroscopyCryo-Electron Facility Josh Monts Todd Schuster, COREManager Instrument COREFacility Theresa Tucker Timothy Lastine Mike Conway Technology Jeff McDonald, Director ofInformation Services Research Support An Le Michelle Jacobson Chrissa Campbell Kim Klukas, Supervisor Group Research Support SUPPORT UNITS: Donglian Liu Qing Li Visiting Scholar Yuanguo Wang Xianghu Wang Hormel Fellow Ningling Kang,AssociateProfessor Metastasis Tumor Microenvironment& Wei Shi Hormel Fellow Bin Liu, Assistant Professor Transcription &GeneRegulation Mehedi Hasan Researcher 1 James Thompson Researcher 5 Amer Alam, Assistant Professor Transport Structural BiologyofMembrane Stephanie Holtorf Researcher 2 Rebecca Morris, Professor Stem Cells&Cancer

Emma Rector, ComputationalCancerGenomics Caitlin Lura, StemCells&Cancer Katie Waller, CancerEpigenetics&Experimental Mike Petersen, Chromatin &EpigeneticGene Abigail Schammel, Transcription &Gene Trinity Gray, CancerCellBiology&Translational Tressie Kinney, Cellular &MolecularBiology Willrodt,Mary CancerStemCells&Necroptosis Kelly Van Hooser, MolecularBioengineering& SURE Interns Andy Lucas, Library Assistant Library Kathi Finley Michelle Hjelmen Brenna Gerhart Public Relations Gail Dennison, Director ofDevelopment & Development &PublicRelations Julie Gerstner Nyayow Dong Stephanie Blaser Becky Earl Minda Anderson Ann M.Bode, Interim Executive Director Office Therapeutics Regulation Regulation Research Cancer Vaccine

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