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LUDWIG LINK | DECEMBER 2020 LETTER Senior Vice President for Communications President Vice Senior Rachel Reinhardt reading! Happy 23. and 22 pages on said they what out Find pandemic. COVID-19 the for Speed Warp Operation with did government U.S. the as much cancer, of types major for immunotherapies other and vaccines the of development therapeutic to accelerate aprogram of feasibility the about colleagues your of afew asked we section, ascientist Ask our In 17. page on begins which Q&A, Yang our in about more learn You can Oxford. Ludwig of Member newest the Shi, and Yang Committee, Advisory Scientific the joined recently has who Merchant, to Juanita community the introduce we researchers, Ludwig-affiliated by earned honors and awards the of some of coverage usual the with Along exploited to treat triple negative breast cancer. be might that interaction lethal” “synthetic of a identification machinery of cell motility and stall cancer metastasis and the the up to gum target drug apossible radiotherapy, following preventing the recurrence of an aggressive brain cancer which of include a reports potentially new approach to briefs, research issue’s this in that of proof ample There’s results. publish and work their to continue ways creative

pandemic, our researchers found COVID-19 the accompanied have that inconveniences sundry and distancing social Despite the lockdowns, Ludwig Link. of issue December to the Welcome 3 LUDWIG LINK ludwigcancerresearch.org Yang Shi of Ludwig Oxford Ludwig of Yang Shi cover: the On News roundup News member newest Oxford’s udwig Committee Advisory Scientific the oining move the on People Tattersall artin In memoriam immunology or transformative achievements or outstanding distinctions and Awards TABLE OF CONTENTS Required reading ascientist Ask Yang with Shi Q&A diagnostics for tapped APS news Company ssumption undone screen peedy eartbreaking signals intervention ietary angerous malingering arget: triple-negative breast cancer reconversion herapeutic map murine lemental twofer ellular enhancement ouse synergy eadly axis n evil angerous circles motion rozen onditional vulnerability repression of ubtleties loss ddressing L J M F F T A S H D D T T E C M D A D F C S A

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LUDWIG LINK | DECEMBER 2020 Awards distinctions and gene expression. These complexes are are complexes These expression. gene modulate dynamically thereby and machinery, gene-reading cell’s to the DNA of availability and packaging the remodeling complexes, which regulate chromatin SWI/SNF abnormal and normal of characterization functional and biochemical pioneering her for recognized was May. in Cigall Lectureship Memorial Takamatsu Princess AACR 2020 the received Tyler Jacks Co-director MIT Research,Cancer respectively; Ludwig Achievement in Clinical Outstanding for Award Burchenal AACR-Joseph 2020 the and Research Cancer Basic in Achievement Outstanding for Award AACR 2020 the received Wolchok Jedd MSK’s Ludwig and Kadoch Cigall Harvard’s Ludwig June, In (AACR). Research Cancer for Association American the by contributions scientific their for recognized Three Ludwig researchers were OUTSTANDINGFOR ACHIEVEMENTS Ludwig Harvard Cigall Kadoch

Ludwig MSK Ludwig Jedd Wolchok

and Cigall will give hers virtually in 2021. in virtually hers give will Cigall and Meeting, Annual AACR 2020 the at lecture avirtual Tyler gave cancer.” of prevention on the detection, treatment, diagnosis, or impact afar-reaching have may or “had have contributions whose to ascientist The prestigious lectureship is awarded progression. tumor of regulation immune the and death, cell genes, suppressor discoveries related to tumor oncogenes, his for and tumorigenesis, of study the for models mouse sophisticated of development prolific laboratory’s his for recognized was Tyler, meanwhile, immunotherapy. cancer blockade checkpoint of era current the in usher helped that work subsequent of a raft for and melanoma, for immunotherapy anti-CTLA-4 of development clinical the in leadership his for recognition received Jedd developmental and disorders. cancer human in disrupted frequently 4 Ludwig MIT Tyler Jacks

LUDWIG LINK | DECEMBER 2020 Awards distinctions and Ludwig Lausanne Ho Ping-Chih by the poor communication from his physicians. The The physicians. his from communication poor the by dismayed was Martin 1990s, the in accident skiing fatal anear- following Hospitalized career. his of course the over articles scholarly 480 publishing clinic, the in cancers—and of variety awide of pathology molecular and cytogenetics the explored he laboratory—where the in both field, chosen to his enormously contributed He 1987. in closed it until Branch the led and 1979 in director its named year, was same that Branch Ludwig the joined Martin 1977, in Sydney of University the to Recruited Australia. Sydney, in 30 August on died Research, Cancer for Institute Ludwig the of Branch Sydney the of director was who Tattersall, Martin MEMORIAM:IN MARTIN TATTERSALL

susceptible to checkpoint blockade. More More blockade. to checkpoint susceptible tumors resistant expression, making UCP2 diabetes that rosiglitazone, spurs drug a identified also They immunotherapy. blockade to checkpoint susceptible more into them their making microenvironment, cells immune anti-tumor key draw UCP2 as known enzyme ametabolic expressing discovered tumors that melanoma colleagues his and Ping-Chih example, for 2019, In therapy. cancer for disrupted be can chatter molecular that how and influence theanti-cancer immune response tumors of adaptations metabolic the which explores how immunometabolism, of field to the contributions his of recognition in August in STAR award Old J. Lloyd CRI Institute Research a Cancer received Ho Ping-Chih Lausanne’s Ludwig TRANSFORMATIVEFOR IMMUNOLOGY 5 countries. countries. developing in to physicians oncology medical teach to widely traveled and researchers and oncologists students, medical Australian of a generation mentored He 2000s. early the in Iraq in behalf their on worked and years 20 than more for committee cancer Organization’s Health World the of a member was Martin adventurer, and traveler world A lifelong doctors, clinical researchers and medical institutions. and patients cancer between communications of outcomes and optimization dynamics, language, the experience, and his research increasingly focused on patient the in interest his intensified experience immunotherapy. and immunology to cancer value transformative potentially of research original in highly scientists engaged mid-career to years five over million $1.25 grants STAR award The melanoma. of model amouse in blockade checkpoint of effects the to boost exploited be could findings These fitness. mitochondrial their disrupting by cells T CD8 infiltrating antitumorhampers responses in tumor- instress the tumor microenvironment metabolic that showed they October, In tissues. other in counterparts their tumor microenvironment without affecting the within Tcells regulatory as known cells depletesselectively immune suppressive CD36 protein cell-surface the blocking that showed team his and Ping-Chih recently

LUDWIG LINK | DECEMBER 2020 People on the move Ludwig Oxford Yang Shi Scientific Advisory Committee Institute Ludwig Merchant Juanita

other histone demethylating enzymes and other and histone demethylating enzymes many identified since has laboratory Yang’s models of genomic regulation. longstanding altering irreversible, modifications such a that dogma 40-year-old considered from upended histones. Their discovery marks methyl erases that LSD1, enzyme, an characterized and identified colleagues his Yang and 2004, In cancers. of variety to awide contribute processes those in the expression of the genome. Aberrations itsand histone protein packaging—control chromatin—DNA to made modifications chemical how explores which epigenetics, of field the in Yang aleader July. is in Oxford Ludwig of Member appointed was Yang Shi MEMBERLUDWIG NEWEST OXFORD’S gastric to improve biomarkers of use Prevention, the she is potential studying for Cancer Native American Partnership the in aco-investigator Tucson. As Arizona, of University the at hepatology chiefand of and gastroenterology professor and clinician apracticing also is Juanita cancers. intestinal and gastric of infection contribute to the development Helicobacterand pylori inflammation molecular mechanisms by which chronic contributions to our understanding of the researcher, Juanita has made notable cancer and AResearch. gastroenterologist Cancer for Institute Ludwig the of Committee Advisory Scientific to the appointed was Merchant Juanita July, In COMMITTEE ADVISORY SCIENTIFIC THE JOINING 6

designed to encourage a healthy diet. diet. ahealthy to encourage designed by ofsponsored the Arizona University Council. Juanita also hosts cooking classes the on serves currently she which for Medicine, of Academy National the of and Sciences and Arts of Academy American the of member is She fellow. a research was also she where Boston, in Hospital General atresidency the Massachusetts her completed and 1984 in University Yale from PhD MDand her earned Juanita communities. Native American underserved and physicians between sensitive interactions effective and culturally respectful, to ensure how on Helicobacter pylori with in diagnosis Nativecancer Americans with him on Page 17 of this issue. this of 17 Page on him with interview our out check Yang, about more To learn Sciences. and Arts of Academy American the of a member and Science of Association for theAmerican Advancement the of afellow is He University. Princeton completedand his postdoctoral at training obtained his PhD from New York University He School. Medical Harvard at pediatrics of professor Waddington C.H. and biology cell of professor Yang was Ludwig, joining to Prior proteins. into transcripts gene of translation the influence possibly and RNA methylate that enzymes discovered has therapy.cancer More recently, his group for trials clinical in now are inhibitors LSD1 . She is also working working also is . She

LUDWIG LINK | DECEMBER 2020 News roundup News neural development to treat the cancer. the to treat development neural normal restore that targets drug identify to model their to use plan researchers resembled that in observed ATRT. The which state, cell anormal maintaining terminal differentiation a and defect in pressure that a causes resistance to differentiation neural and loss SMARCB1 between interaction an identified team his and Frank tissue. brain of mimics cultured either organoids— or neurons cerebral onloss the differentiation of the into cells that of effects the studied and demand on SMARCB1 to lose cells stem pluripotent researchers engineered human induced development.SMARCB1 neural affects The the of loss the gene tumor suppressor how described Furnari Frank Diego’s San & Development paper aSeptember In packaging). protein its and DNA for term collective by chromatin remodeling (theprocesses regulate gene expression in developmental helps which complex, BAF the of subunit a SMARCB1, called agene of inactivation to linked primarily is cancer The younger. or years three children strike usually and begin in the cerebellum or brain stem ATRTs of half About cord. spinal and brain the of cancers fast-growing and rare are (ATRT) tumors rhabdoid teratoid Atypical ADDRESSING LOSS , a team led by Ludwig Ludwig by led , ateam in Genes in Ludwig San Diego San Ludwig Frank Furnari Skirmantas Kriaucionis Ludwig Oxford 7

strategy for cancer therapy. cancer for strategy effective an be might inhibitors methylation DNA with HDAC inhibitors combining suggests This genome. the of regions some on redundantly act can they although independently,HDACs function largely and methylation DNA that report They gene and expression. factors transcription of occupancy the accessibility, chromatin affect events epigenetic two the how studied researchers Tothe out, find deacetylation. of independent effects than rather HDACs of activity downstream to the due is methylation DNA of effect been unclear how much of the repressive Yet has it therapies. cancer for targets are (HDACs).deacetylases Both processes protein complexes containing histone and indirectly, by recruiting repressor genes, of reading the initiate which factors, by altering the binding of transcription directly, both acts former The repression. gene histoneand deacetylation—of methylation mechanisms—DNA epigenetic of two the analysis reported Kriaucionis Skirmantas Oxford’s Ludwig by led team September a In apuzzle. been has functionally collaborate they how but access, to govern structure its to alter known are chromatin to modifications epigenetic, or chemical, Numerous genes. transcribe that enzymes moleculeswith and the regulatory interaction enables Accessibility chromatin. called astructure into packed and spools protein around wound is which to DNA, access managing by is expression gene regulate cells which in way important One REPRESSION OF SUBTLETIES paper in Genome in Research

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LUDWIG LINK | DECEMBER 2020 News roundup News demonstrated that specific cancers might indeed indeed might cancers specific that demonstrated Meitinger Franz and Desai Arshad Karen, by led team Nature in reported astudy In division. their block not did but cells cancer of panel abroad from centrosomes deplete reversibly essential for centrosome formation, could enzyme an PLK4, of inhibitor specific ahighly centrinone, that Science in reported Shiau Andy and Oegema Karen by led researchers Ludwig as centrosomes, lack they when segregation—even complete can cells that process—chromosomal cancer of types many But division. cell of stages late the in cells to daughter chromosomes of numbers equal out that help organelles parcel Centrosomes cellular are CONDITIONAL VULNERABILITY Diego San Ludwig Oegema Karen in September, a Ludwig San Diego Diego San aLudwig September, in in 2015. That study found found study That 2015. in Ludwig San Diego San Ludwig Andy Shiau

8 Molecule program. Discovery Small Ludwig’s and Shiau Andy by development under treatment with an improved PLK4 inhibitor, like those to to respond likely cancers of amarker as serve could over-expression TRIM37 that showed and vulnerability this of mechanism the detailed researchers The TRIM37. with known chromosomal abnormalities overexpress neuroblastomas and cancers breast of subsets Notably, conditions. such under proliferating however, stop TRIM37, of levels high with cells Cancer inhibition. PLK4 despite dividing continue cells cancer levels, low at is enzyme this When TRIM37. ligase ubiquitin the enzyme, asecond of presence the on depends showed, they sensitivity, That inhibition. to PLK4 sensitive be Ludwig San Diego San Ludwig Arshad Desai

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LUDWIG LINK | DECEMBER 2020 News roundup News with radiotherapy orwith chemotherapy. radiotherapy animals in activation NM2C of combination the to evaluate hope and metastasis target—NM2C—against adruggable have now researchers the adrug, as to work likely not is 4-HAP Although counterparts. to untreated compared tumors of burden the reduced significantly 4-HAP with animals the dosing metastasis, liver for model amouse in spleen the into were cells injected colon cancer When migration. cellular of machinery the up gumming filaments, actin of types certain on it freezes activation abnormal NM2C’s that hypothesized colleagues and Ralph Ronald, microscopy, elegant some from evidence of basis the On motility. cell in role acentral play that filaments actin as known cytoskeleton the of components organizes and cells of stiffness the control helps protein This (NM2C). myosin-2C nonmuscle called cell cancer the in aprotein activating by migrate and shape to change cells cancer of ability the compromises (4-HAP), a compound, 4-hydroxyacetophenone that reported They process. the hamper to way new apotentially of Sciences Academy National ofthe Proceedings described Chicago of University the of Rock Ronald and Weichselbaum Ralph Co-director Chicago Ludwig by led researchers of ateam August, In deaths. cancer-related all of 90% approximately causes Metastasis MOTION FROZEN in the the in Ludwig Chicago Ludwig Ralph Weichselbaum Ludwig San Diego San Ludwig 9 Paul Mischel

develop such therapies. develop such to plans that Bio, Boundless astartup, of co-founder is Paul dividends. significant yield could therapy cancer for ecDNA those without, so strategies that target than outcomes survival five-year worse significantly have amplification ecDNA with Patients oncogenes. for enriched significantly to be found were ecDNAs The cancers. gastric and neck and head and esophageal, ovarian, lung, bladder, sarcoma, glioblastoma, cancer brain the as such cancer, of forms malignant most the in frequently more much and tumors, 14% in human of minimum at occurs ecDNA that found team his and Paul be. might impact clinical its what and types cancer across is ecDNA common how clear entirely wasn’t it But resistance. drug drive often which tumors, in heterogeneity cellular high and evolution tumor accelerated with associated is and cells healthy in seen ever hardly is ecDNA his colleagues have previously shown that and Paul cancer. of types multiple across associated with poor patient outcomes is (ecDNA), DNA extrachromosomal or nucleus, the in DNA of circles free-floating on located genes cancer of amplification the that showed colleagues and Mischel Paul Diego’s San Ludwig August, in astudyIn DANGEROUS CIRCLES DANGEROUS Genetics Nature in reported

LUDWIG LINK | DECEMBER 2020 News roundup News Kyn-AhR pathway activation. IDO/TDO- showing or TDO IDO, expressing tumors with patients for medicine personalized of abasis be could and trial aclinical in tested be should combination the suggesting immunotherapy, blockade PD-1 with combined is treatment the when amplified is effect This mice. in growth tumor slows and suppression immune AHR inhibitor reverses IDO/TDO-mediated an with axis this Targeting macrophages. between Tregs and tumor-associated interplay an from stems found, they of suppression, mechanism immune This blockade. checkpoint to immune resistance drives pathway signaling AHR the that showed colleagues Taha their and Jedd, activity. anti-tumor their dampens which PD-1, to express Tcells killer prompts cells—and suppressor derived (Tregs) myeloid and Tcells regulatory cells— generation of immune suppressive the to drive microenvironment tumor the in AHR with interacts L-kynurenine, activity, IDO/TDO of Aproduct inhibition. its of effects the examined and tumors such in activated selectively is signaling Nature Communications paper August an in reported study, The cancers. of variety awide in suppression immune with associated enzymes TDO, and IDO of levels high express that tumors in responses immune anti-tumor receptor (AHR)hydrocarbon suppresses aryl the which by mechanism the Merghoub and their colleagues described Taha Wolchok, Jedd MSK’s Ludwig AXIS EVIL AN , found that AHR AHR that , found in in Taha Merghoub MSK Ludwig Jedd Wolchok Ludwig MSK Ludwig Ludwig San Diego San Ludwig Richard Kolodner 10

variety of malignancies. a to treat drugs for target anovel as FEN1 identify findings These well. as genes other with interactions lethal synthetic has FEN1 that indicating deficient, BRCA were treatment to C8 responded that tumors and lines cell cancer the all not Notably, tumors. C8-resistant the not but tumors C8-sensitive the of growth the inhibited significantly C8 that showed and mice into tumors C8-resistant and C8-sensitive grafted then researchers The cells. such of killer effective an to be proved and loss FEN1 of effects the replicated C8, synthesized, they molecule FEN1-blocking drug-like a Similarly, mutations. BRCA with cells to cancer deadly is repair, and replication DNA for important is that gene amammalian FEN1, removing or disabling that discovered team Richard’s cells, yeast on studies their from Building death. cell survival—causes to cell vital own its on is which of genes—neither two of mutation the when occurs lethality Synthetic cancers. other and ovarian genes, which are implicated in breast, 2 and BRCA1 their in mutations with cancers in therapy for exploited be might that interaction lethal” a“synthetic July ofSciences Academy National of the reported colleagues and Kolodner Richard Diego’s San Ludwig DEADLY SYNERGY in the Proceedings the in in in

LUDWIG LINK | DECEMBER 2020 News roundup News gene expression programs that give give that programs expression gene the detailed colleagues her and Arber publication Science Advances aJuly In cells. cancer of destroyers potent are that Tcells killer CD8 cells, these of markers distinguishing the and receptor antigen Tcell akiller of cells be can engineered—with the addition T helper But development. under and use in now immunotherapies cancer of focus primary the are Tcells Killer response. immune the of aspects multiple managing and orchestrating generals, like are Tcells helper while cells, cancerous and infected of assassins the are Tcells killer things, of scheme system’s immune the In TWOFER CELLULAR availability. nutrient of asensor as works PHD3 cells healthy in that show they study, this In fat. burning on dependent cells cancer of types some makes PHD3 of loss the that shown previously had team her and Marcia mice. in endurance exercise boosts dramatically PHD3 of adeficiency that found they intriguingly, Most switch. that making in PHD3 enzyme the by played role central the detailed colleagues her and Haigis Marcia investigator Harvard Ludwig July, in apaper In fats. to burning over switch however, they on nutrients, energy. short When to generate sugars burn typically Cells ENHANCEMENT MOUSE α and and Metabolism Cell in published β , Ludwig Lausanne’s Caroline Caroline Lausanne’s , Ludwig —to helper- generate hybrid

uptake during exercise. exercise. during uptake oxygen maximum of ameasure max, VO2 higher amuch boasted and counterparts unaltered their than longer 40% and farther 50% run could They endurance. exercise enhanced showed PHD3 to lack engineered Mice metabolism. fat drive activity—to PHD3’s from it shields that modification chemical adifferent with it tags ACC2—and activates AMPK named enzyme an drops, supply nutrient the when But energy. for burned are they where mitochondrion, the into fats of passage the to curtail ACC2, enzyme, another inhibits and modifies chemically PHD3 abundant, are nutrients When cellular immunotherapies.cellular of types other in used Tcells of potency the to improve applied be can that insights provide but therapy, cancer for T cells hybrid such of design to the contribute only not findings The proliferation. for primed and to exhaustion resistant more to be appear they that example, for efficacy—showing, heightened their for to account appear that cells hybrid the in activated programs genetic multiple identified researchers the Tcells, killer regular of to those them comparing and Tcells helper-killer hybrid individual of patterns expression gene global the profiling By potency. their hybrids these 11 Ludwig Harvard Marcia Haigis Ludwig Lausanne Caroline Arber

LUDWIG LINK | DECEMBER 2020 News roundup News Ludwig Lausanne Joyce Johanna Diego San Ludwig Ren Bing

and their M2-like phenotype is further further is phenotype M2-like their and radiotherapy, of course initial an following mice in tumors GBM into flood MDMs and MG both found researchers The growth. tumor which they support phenotype—in M2-like state—the activation alternative an into both push can Gliomas body. the patrol ordinarily which (MDM), macrophages (MG), and recruited monocyte-derived brain’s resident macrophages, microglia the both harbor Gliomas recurrence. GBM to control reprogrammed be might cells these how showed and tumors (GBM) glioblastoma in macrophages as known cells immune affects radiotherapy Translational Medicine reported colleagues and Ludwig Johanna Lausanne’s Joyce RECONVERSION THERAPEUTIC Integrating these data revealed the activity mice. in stages developmental eight of course the over types tissue distinct 12 in machinery regulatory and reading gene cell’s to the DNA of accessibility and expression) gene regulate that marks (chemical modifications histone the gene expression patterns, charted studies the of one led Ren Bing Diego’s San the human and mouse genomes. Ludwig the DNA regulatory sequences across detailing of papers its third installment July in published just project (ENCODE) ofThe Encyclopedia Elements DNA ELEMENTAL MAP MURINE reported in Nature in reported in July how how July in Science Science in . Bing’s study study . Bing’s 12 of a variety of diseases. of avariety of study the for models mouse of use the for diseases and have implications reassuring developmental of anumber of origins genetic the on light shed findings The sequences mapped on the mouse genome. share evolutionary origins with regulatory that genome human the of regions in located are diseases human of a variety discovered that genetic for variants risk They development. fetal mouse of stages regulate their expression across various that sequences DNA candidate 500,000 than more and stages developmental and tissues across genes of thousands of such drugs in clinical trials. clinical in drugs such of regimens dosing and evaluation the for implications have may which improvement, atransient only in resulted radiation plus (for days) 12 inhibition CSF-1R term short- contrast, By alone. radiotherapy of three nearly weeks with observed mice, compared to increase a survival the of 95% for study the of months six full the through survival extended TAMs and radiotherapy effectively reprogrammed following inhibition CSF-1R of regimen adaily that to show drugs these of one used they study, current the In phenotype. M2-like the reverse can inhibitors CSF-1R Johanna’s lab has previously reported that them. within predominate that MDMs is recur, it gliomas the When exacerbated.

LUDWIG LINK | DECEMBER 2020 News roundup News notoriously difficult to treat. to difficult notoriously negative breast tumors, which remain triple- in cells stem cancer disable that drugs of development the for atarget be might LEFTY1 suggests This proliferation. for LEFTY1 on dependent highly are out, turns it cells, Such proliferation. cell drive signal—to BMP7 the of transducer BMPR2—a named aprotein with interacts LEFTY1 cells, stem cancer breast in that triple-negative revealed breast cancer of xenografts in BMP7. Studies named aprotein by cells stem to mammary transmitted signal anti-proliferative an opposes protein The cells. stem epithelial mammary malignant and normal both of progenitor proliferation drives and cells mammary by produced is found, they LEFTY1, cancers. breast certain of genesis the in as well as maintenance and development breast in role acentral plays and SMAD2 inhibits LEFTY1, cells, stem mammary by secreted afactor that July reported colleagues and Clarke Michael researcher Stanford Ludwig cavities. body line which cells, epithelial of maintenance optimal and involved in controlling the proliferation are pathway SMAD the to as referred cascades signaling intracellular of A set CANCER BREAST TRIPLE-NEGATIVE TARGET:

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most significantly. most mice of survival the extending inhibitor the mouse model, with an approved PI3K in inhibited PI3K tumors signaling and MEK target that drugs of anumber that proliferation. The researchers reported to cell conducive pathway additional an fueling and its signaling prolonging receptor, EGF the of movement the suspends out, turns it INPP4B, of loss The digested. and degraded or surface to the returned either is it until signaling continues and internalized is receptor EGF the activated, is it After tumors. the in active potently also MEK—was named aprotein through signals which receptor, EGF the by proliferation—driven cell drives that pathway additional an surprisingly, But, pathway. signaling PI3K/AKT the of activation abnormal an displayed tumors those from cells expected, As mice. the in developed tumors more the INPP4B, of levels the lower the that showed and genes INPP4B its of both or engineered mouse model that lacked one agenetically developed team The INPP4B. suppressor tumor the of loss the by characterized are tumors TNBC all of 80% of About triple-negative breast cancers. proportion alarge drives that mechanism molecular anovel described Liu Hui Toker alumnus Alex and investigator Harvard Ludwig by led researchers In a June Cancer Discovery aJune In MALINGERING DANGEROUS

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LUDWIG LINK | DECEMBER 2020 News roundup News Ludwig Stanford Weissman Irv proliferate, they also express high levels levels high express also they proliferate, cell that of descendants the As well. as plaques human in detectable event cell begins to multiply abnormally—an muscle smooth asingle model, mouse a in formation plaque of stages early the in that discovered researchers The plaques. atherosclerotic of formation the in role acentral plays vessels blood line that cells muscle smooth of proliferation study Their atherosclerosis. and cancer between Sciences of Academy National ofthe Proceedings the in reported Leeper Nicholas colleague Stanford his and Weissman Irv Stanford’s Ludwig by led A team SIGNALSHEARTBREAKING CD47 boost cells human and mouse that found colleagues his and Irv cells. sick up gobble otherwise would which macrophages, as known cells immune to signal me” eat a“don’t transmits cells, cancer of variety abroad by expressed is shown have team his and Irv which CD47. protein, named This aprotein of step tuberculosis upcauses expression that one the like bacteria and COVID-19) (including SARS-CoV-2, which causes viruses many with infected cells that reported Health of Institutes National the at colleagues and Weissman Irv by led Stanford Ludwig from researchers paper aJune In DIETARY INTERVENTION in June an intriguing similarity in similarity June an intriguing revealed that an abnormal in mBio in , a team of of , ateam 14 cardiovascular diseases. treatment, could also be applied to treat acancer as developed already have team his and Irv which CD47 blockade, suggests This cells. proliferating the to clear macrophages their of ability the restored and mice in levels C3 reduced gene its deleting or CD47 expression down Knocking well. as cells cancer by employed tactic to macrophages—a signal me” eat a“don’t transmits which CD47, of expression their up step also they that but macrophages system’s immune the by cleared be normally would cells inflammatory proliferating, with atherosclerotic These plaques. associated factor inflammatory an C3, of resistant tuberculosis. tuberculosis. resistant drug- multiple and COVID-19 like diseases infectious to treating approach a new opens finding The bacterium. tuberculosis the by to infection resistant more far were CD47 lacking mice Further, meningitis. causes that avirus by infection of stages all in load viral suppress could cancers multiple against trials clinical in now is that colleagues and Irv by developed one to to CD47 analogous antibody an that showed also They uncontrolled. when inflammation systemic deadly, cause can which response, immune mounting the over control of ameasure as likely infection, of 24 hours within expression

LUDWIG LINK | DECEMBER 2020 News roundup News the personalization of cancer therapy. of cancer the personalization improve help could technology new This model. amouse in growth tumor delayed that combination drug a identified cancer colorectal of avatars mouse on screens Similar time. over evolve and adapt cultures such of cells the since days, several for grown samples on missed been have might but tumors the shrank that drugs identified and mice from tumors breast fresh in drugs 1,650 to screen HT-DBP used colleagues his and Anthony signaling. apoptotic inducing in active as identified are peptides to BH3 sensitive that render mitochondria more Drugs to adrug. exposure following domains— BH3 their proteins—specifically, driving mitochondria to of apoptosis- fragments tumor HT-DBP exposes to apoptosis. cells drive cells—that of generators power-within mitochondria—the molecules between balance changing the measuring on relies It apoptosis. or death, cell to programmed are cells tumor determines how individual close technology microscopy-based the DBP), (HT- profiling BH3 dynamic throughput high- aday. Named within often patients, cancer from taken freshly samples tumor against drugs of to thousands hundreds screen swiftly can that a technology describe colleagues and Bhola Patrick Letai, Anthony Harvard’s Ludwig In a June paper aJune In SCREEN SPEEDY in Science in Signaling,

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Molecular Cell Molecular in June development. The study and tumorigenesis influence can that genes of control the and availability factor transcription of fine-tuning allows BRAF, as such oncogenes by controlled mechanism, redistribution This not. does acetylation to such resistant mutant ahigh-affinity whereas tumorigenesis, drives and development melanoma supports acetylation mimics that mutation MITF low-DNA-binding-affinity a that finding their explains This sites. regulatory actual to its binding its of likelihood the increases so and sites background of reservoir this from it releases DNA-binding MITF’s Weakening genome. the in sites affinity, low but similar, of background ahigh against sites regulatory to find need factors transcription that argue researchers occupancy of sequences. regulatory The MITF’s increases actually to DNA, binding its weakens which acetylation, as known to MITF modification achemical that showed They true. always isn’t this that amodel, as MITF factor transcription using the melanoma-associated demonstrated, has Goding Colin Oxford’s Ludwig by led ateam Now function. their sequences, the better they perform DNA regulatory these bind they tightly more the that assumed typically is It agene. of regions regulatory the bind factors transcription as known proteins process, the To start expression. gene in one step is Transcription UNDONE ASSUMPTION . was published in in published was

LUDWIG LINK | DECEMBER 2020 early-stage cancer in blood tests tests blood in cancer early-stage to detect designed is Oxford, Ludwig at developed technology, The million. $410 for Sciences Exact by acquired was (TAPS), assisted pyridine borane sequencing to commercialize a technology, TET- Research Cancer Ludwig by granted alicense with 2020 June in launched BaseLudwig Genomics, spin-off TAPS TAPPED FOR DIAGNOSTICS 3. November on Zoom via Genomics Base of sale the celebrated office York New the and Oxford Ludwig of Members Company news Company in Chunxiao Song’s laboratory laboratory Song’s Chunxiao in detection of cancer. of detection early the for people of screening routine even perhaps eventually, and, therapy cancer undergoing patients in responses continuous monitoring of treatment Genomics hopes to develop would permit Base sort the of biopsies Liquid DNA. tumor circulating of amounts trace to made modifications epigenetic of detection sensitive highly the through 16

LUDWIG LINK | DECEMBER 2020 LUDWIG OXFORD’S NEWEST MEMBER NEWEST LUDWIG OXFORD’S YANG SHI Q&A 17 opportunity to forge close interactions interactions close to forge opportunity the of because to Oxford attracted initially Iwas home. my is Boston because make to decision easy an wasn’t it honest, to be But town. alovely is Oxford and science, to do place afantastic is Oxford Ludwig Branch? Oxford the to join you motivated What industry. biotech and pharmaceutical to the transitioned successfully have who or academia in labs own their to start on gone have who scientists of generations new of training to the contributed has lab my that fact the is proud very me makes what discoveries, to scientific addition In immunotherapy. blockade to checkpoint susceptible more tumors make may LSD1 inhibiting that to find excited We were immunotherapy. to responses tumor and immunity antitumor in regulation epigenetic in We’ve recently become interested differentiation like diseases and cancer. development, in roles critical have which demethylases, histone other many identified also have others and we LSD1, to addition In irreversible. and static were modifications these that dogma 40-year a overturned This regulated. dynamically is methylation histone that showed which eraser, methyl histone first LSD1—the of discovery the is out stands that one The accomplishments? research and discoveries exciting most your were what Research, Cancer Ludwig to joining Prior

LUDWIG LINK | DECEMBER 2020 Q&A the fact that core funding is provided by by provided is funding core that fact the on based also was decision my terms, practical In bedside. to the translated be can findings basic these of some how seeing in interest of alot Ihave but scientist, abasic I’m collection. sample clinical to expand and recruitment patient up to speed countrywide centers multiple at conducted to be studies clinical-related allows This country. the across patients cancer all for protocols treatment unified are there (NHS), Service Health National UK to the due that is understanding My clinicians. with 18 underpinnings of how things work work things how of underpinnings basic the in interested fundamentally still Iam because Yes No, no. and research organization? acancer joined have you that now changed years 10 next the in accomplish to like would you what of vision your Has to lose. time questions waiting to be addressed and no many so are way. There expeditious and efficient an in forward science the move Ican how and problems about to think time free more me give will This Ludwig.

LUDWIG LINK | DECEMBER 2020 is to understand these pathological pathological these to understand is goal our and lab, science abasic We are care? patient cancer impact research your will How therapy. responsepatients’ to checkpoint blockade impact both which system, immune host the and tumors the in play factors epigenetic role what understanding in interested We are therapy. blockade responses to immune checkpoint sustained to generate ways and ‘hot’ tumors ‘cold’ turn to ways to find order in regulators epigenetic exploring also We’re beneficial. therapeutically be potentially can that differentiation cells induces of cancer epigenetic regulators whose inhibition identifying in interested We are AML. and DIPG both in role acrucial to play shown been has Epigenetics (AML). leukemia myeloid acute (DIPG) and Glioma Pontine Intrinsic Diffuse in modifiers epigenetic of role the studying is lab Yes. Our Oxford? in apriority be still glioma and leukemia myeloid acute Will cancer. on more focus to lab my to allow to re-prioritize have may we to Oxford, moving after But disability. mechanisms underlying intellectual epigenetic the to understand cells patient and models mouse with working also are we to cancer, addition in lab, Boston my In cancer? on focused more being on elaborate you Could cancer. on focused more even be Iwill now because yes, And biologically. Q&A strategies. treatment better to design us allow will that level the at them to understand need we so diseases, many is cancer that know We cancer. understand to really clinicians and scientists between interactions the to enhance need we time, same the at But to cancer. lead that processes different the control that mechanisms basic the of understanding asolid to have We need care? patient and research epigenetics in order to advance cancer in needed are breakthroughs What care. patient on impact greater to translate will Oxford in clinicians the between basic science researchers interactions closer forging that believe Ifirmly And therapy. cancer for targets new uncover also but mechanisms, fundamental the about more learn we will only not doing, so In cancer. in regulators epigenetic of action of mechanisms and role the addressing by processes response to checkpoint blockade therapy. patients’ both which system, impact immune the host and epigenetic in the tumors play factors role We what interested are in understanding 19

LUDWIG LINK | DECEMBER 2020 Q&A Q&A doors for developing specific, targeted targeted specific, developing for doors diseases and hopefully opened some human other and cancer understanding for implications have that processes biological basic some uncovered I’ve difference. asmall to make able been I’ve Ithink where one also it’s but curiosity my satisfied has that acareer is research that self younger my tell Iwould started. only Ihave if as Ifeel years, many for lab my had Ihave Although it. Ilike more the it, Ido more the But research. in career a to pursue plan initially not Idid design. by not often are that life in happen Things career? your about yourself tell you would what yourself, of version 10-year-old to the talk could you If 20 research? in acareer with up end you did How career? this to follow you inspired that particular in something there Was therapeutic strategies. new of development to the contributing by humankind help ultimately will I do what Ihope cancers. against therapies else. anything for it trade Iwouldn’t research. in landed to have lucky very really I’m But to me. happened that of None basement. the in experiments science doing years early their spent or age young a very from science loved they that you tell may research into go who people Many

LUDWIG LINK | DECEMBER 2020 at this moment. I like to read, and I enjoy Ienjoy and to read, Ilike moment. this at unthinkable almost seems which science, doing Istop once science as much as things other enjoy and to do able to be want I foremost. and first That’s hobby. your is science science, in you’re When science? outside hobbies any have you Do completing a research project. and initiating for blueprint asolid have they so interests, their form them to help discussions ongoing have we projects, interests their directing and research their to develop freedom the them giving While act. abalancing it’s But about. passionate and in interested truly are they what out to find them with Iwork passion. and interest research their develop to free to be members lab my I want lab? your running for philosophy guiding your is What world. their in role important an play to Iget training. PhD their of out coming just fellow apostdoctoral or student a PhD as either years their of part development, career their of apart to be me allow They do. they what about passionate and work with young people who are creative always you Second, them. of some into look and ahead go Ishould and questions, interesting and important really are those say, and to talks listen papers, read You can restricted. You feel never questions. those address to ways find and questions important to pursue me allowed has and career free avery is Research curiosity. my satisfied really has it First, research? your of part satisfying most the been has What Q&A

by makes us all feel connected. feel all us makes by close I’m knowing and work at hallways the down and up walking just but home from meetings those do Icould time. the all lab the in rooms separate from We Zoom me. need they if there I’m knows lab my person, in people with meet I can’t though even And regularly. in to go try Istill although time, the all office the in to be have I don’t anywhere. work Ican bench, the at not I’m since And, world. the of part another in or state another in talks cool to really listen and click just also can you home, your of comfort From the amazing. really It’s travel. to have didn’t I because field my of outside are that meetings Harbor Spring Cold several Iattended For example, more. I attend more meetings, virtually. to learn opportunity an had actually I’ve COVID quarantine? the during you for changed has What myself. to amuse instrument an up picking possibly and music, learning on time to spend want Imay and to music, comes it when illiterate completely Iam But music. about. passionate in and interested themare what truly they to out find with Iwork interest passion. their and research to to free be members my develop lab I want 21

LUDWIG LINK | DECEMBER 2020 Ask a scientist a Ask immunotherapies) of for cancer? majortypes the development of therapeutic vaccines (and other it bepossible to to devise accelerate aprogram similarly the of time-horizon preventive vaccine development. Would COVID-19 vaccines, seems to shortened have dramatically Operation Warp Speed, STEPHANIE DOUGAN training. graduate through school elementary level from every at States United the in education to science acommitment and talent international recruit to policy visa welcoming and open an Institute, Cancer National the in investment continued a be would approach government best the immunotherapies, cancer of field the advance To ingenuity. truly and creativity human by fueled are which discoveries, science to basic goes point this at Funding disease. the to fight inadequate are antibodies neutralizing since position, different avery in are vaccines Cancer pipeline. production and development manufacturing, the to accelerate going is sources) industry and philanthropic, government, (from funding of influx The vaccines. COVID-19 of wave first the to implement learned be to needs that new little very is there standpoint, From ascientific protection. to confer sufficient are antibodies neutralizing where viruses, for vaccines preventative making about know-how scientific of generations on based is development vaccine COVID-19 Ludwig Harvard Ludwig San Diego San Ludwig SHOSHANI OFER drug resistance in patients. overcome and efficacy therapy to increase personalized truly treatment cancer making Second, prognosis. improve significantly and detection early enable would types cancer different for screens population massive First, devised. be could strategy atwo-pronged COVID-19, with experience our on Building

which is to fueling the race develop 22

LUDWIG LINK | DECEMBER 2020 Ask a scientist a Ask Ludwig Johns Hopkins KONIG MAX the clinic may be transformative. high-risk, high-reward cancer immunotherapies directly from research labs to translate to willing companies for risk financial and friction regulatory limit that programs marriage, anatural not are speed” “warp and science While time. record in vaccines SARS-CoV-2 to deliver track on are partnerships private public- economy, and life on toll unfathomable an with apandemic Facing Oxford Ludwig EMILY STEFFKE accelerated. be can therapies new of approval federal support, public and backing financial strong with that demonstrated has program However, this trials. to cancer translated easily not is which cohorts, patient non-specific relatively large, recruiting rapidly on depended has success Speed’s Warp Operation mutations. tumor underlying particular with groups patient select only benefit may vaccines cancer most Thus, disease. asingle not is cancer COVID-19, Unlike MIT Ludwig WEINBERG A. ROBERT toxicity. effect nature) may damage normal tissues, creating a clinically unacceptable side- its (whatever therapy immune the since targeted, be cannot such, as body—and, cancer-associated antigens are also displayed cells by throughout normal the many that fact the therapy; to immune response in antigens displayed of display their shift may cells cancer that fact the cells; cancer of proliferation and viability continued the for critical is display whose antigens identifying include by comparison, extraordinarily challenging for a number of reasons. These is, vaccine anti-cancer an However, making technology. existing given trivial, relatively COVID-19), (including viruses most for is, vaccine anti-viral an Making

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LUDWIG LINK | DECEMBER 2020 Required reading A, Ryan J, Zhao JJ, Letai A. Letai JJ, J, Zhao Ryan A, Sotayo D, Cocozziello JM, Cleary AJ, Aguirre K, Ng K, McQueeney MS, T, Pioso O,Hagan Chipashvili J, Ni E, Lavrova E, Su E, Sicinska JL, Guerriero E, Ahmed PD, Bhola therapies in solid tumors. accurately predict effective and quickly may profiling BH3 dynamic High-throughput 16 June 2020 Signaling Science MC. J, Haigis SP, Auwerx Gygi RJ, Shaw LJ, Goodyear NYR, O,Agar Rombold H, Li D, Garcia JA, Paulo A, Clermont A, Dean EC, Randall NJ, German SJ, Wong E, Zaganjor JB, Spinelli Yoon H, skeletal muscle. in oxidation fat and capacity exercise promotes loss PHD3 (Epub) 13 July 2020 Metabolism Cell Ludwig Harvard RR. Weichselbaum RS, Rock DN, Robinson MC, AT, Posner Pearson EC, Poli L, Xue NN, Khodarev MA, Beckett ES, Schiffhauer A, Surcel DG, U, Thomas Cichoń K, Krysztofiak M, Stack DS, Bryan metastasis. reduce to cytoskeleton modulates the actomyosin 4-Hydroxyacetophenone print. of ahead Online 26 August 2020 USA Sciences of Academy National the of Proceedings Chicago Ludwig Arber C. Arber D, Gfeller MK, Brenner PC, Ho N, Varadarajan N, Rufer M, Hebeisen F, T, Wang M, Wu Sadeghi N, Nouraee Yu YR, MA, Paniagua Martínez- I, Gruber E, Hoyer B, Carreres G, Bajwa JA, Rath Tcells CD4+ human CD8α and TCR- of underlying antitumor function pathways multiple identifies Single-cell transcriptomics (eCollection) 3 July 2020 Advances Science JA. Joyce C, J, Watts Westerga D, JT, Brandsma Huse J, Gadiot L, DF, Tillard Quail M, Groot de SM, F, Handgraaf Klemm J, Tessier RL, Bowman L, Akkari overcome resistance. to astrategy as inhibition CSF-1R reveal radiotherapy after populations macrophage glioma in changes Dynamic 15 July 2020 Medicine Translational Science Ludwig Lausanne Toker A. LC, Cantley V, O,Haucke Elemento GM, Wulf AJ, Navarro RC, Geck CJ, Murphy H, Wang MN, Paddock H, Liu cancer. promotes triple-negative breast and trafficking EGFR modulates suppressor tumor INPP4B The (Epub) 8 June 2020 Discovery Cancer β -engineered -engineered 24 Mazza D, Goding CR. CR. Goding D, Mazza Wilmanns M, Steingrímsson E, JP, Lambert I, Davidson EE, Patton X, Lu M, P, Middleton Filippakopoulos B, Böckler Schuster- B, Thomas E, Suer R, Lisle T, R, Freter Strub M, Lu Z, Zeng A, Schepsky H, Friedrichsen V, Pogenberg A, Loffreda R, Louphrasitthiphol P, Siddaway redistribution. acetylation-mediated genomic factor availability through Tuning transcription print) of ahead (Online 4 June 2020 Cell Molecular S. Kriaucionis RJ, Klose BM, Kessler P, Spingardi HW, King M, Cusack factors. occupancy of transcription genomic the to acetylation DNA methylation and histone Distinct contributions of September 22 (Epub) 2020 Research Genome Oxford Ludwig Merghoub T, Wolchok JD. K, McGovern MG, Manfredi AC, J, Castro Cavanaugh D, Zamarin R, Zappasodi C, Liu S, Pourpe L, Mangarin D, Redmond IJ, Cohen M, Gigoux CH, J, Weng Tchaicha S, LF, Budhu Campesato L-Kynurenine by induced axis suppressive Treg-macrophage a restricts AHR the of Blockade August 11 2020 Communications Nature MSK Ludwig Verhaak RGW. V, Bafna PS, Mischel CR, HY, Beck Chang AG, Henssen JH, F, Schulte Menghi E, Yi SB, Amin S, Namburi U, V, Rajkumar J, Deshpande J, Liu Luebeck AD, Gujar S, Wu NP, K, Turner Nguyen H, Kim across multiple cancers. outcome poor and amplification oncogene with associated Extrachromosomal DNA is print) of ahead (Online 17 August 2020 Genetics Nature K. Oegema A, Desai AK, Shiau DA, Jenkins R, Kabeche JV, Anzola RL, Davis S, Watanabe KY, F, Lee M, Ohta Meitinger vulnerability to PLK4 inhibition. cancer-specific controls TRIM37 9(Epub) September 2020 Nature FB. Furnari JR, Crawford M, Kool PD, Johann T, S, Koga Miki AD, Parisian cell stability. impact and maturation block to state differentiation neuronal SMARCB1 loss interacts with print) of ahead (Online 10 September 2020 &Development Genes Diego San Ludwig

LUDWIG LINK | DECEMBER 2020 Required reading Quake SR, Clarke MF. Clarke SR, Quake A, Newman G, Somlo FM, Dirbas L, T, Li S, Sim Kalisky D, Qian AH, Kuo SS, Sikandar M, Adorno K, Sanchez N, Parashurama J, Lam GS, Gulati LS, Heitink J, Antony NA, Lobo M, Zabala Tumorigenesis. and Growth Progenitor Mammary Promotes that Inhibitor aDual-SMAD Is LEFTY1 (Epub) 20 July 2020 Cell Stem Cell Stanford Ludwig JYJ, Kolodner RD. Wang CD, T, Putnam Gahman A, J, Srivatsan Y, Mueller Ishii E, Guo homologous recombination in defects with cancers human for target therapeutic a as endonuclease FEN1 27 (Epub) July 2020 Sciences of Academy National the of Proceedings B. Ren LA, Pennacchio A, Visel DE, Dickel Y, Shen JR, Ecker K, Gaulton W, Wang JM, Cherry H, Yang H, Amrhein D, Trout BA, Williams JY, Han S, Chee S, Y,He Preissl Y, Fukuda-Yuzawa EA, Lee BJ, Mannion AN, QT, Harrington Pham TH, Garvin M, Kato CS, Novak I, Plajzer-Frick JA, V, Akiyama Y, Qiu Afzal JM, Davidson JS, Strattan M, Wang B, Zhang B, Ding A, J, Wildberg Chiou B, AY, Lee H, Y, Li Huang Zhang Y, Zhao I, Barozzi DU, Gorkin development. fetal mouse in landscapes chromatin dynamic of atlas An (Epub) 29 July 2020 Nature NJ. Leeper IL, Weissman E, Ingelsson GK, Owens JLM, Björkegren S, Koplev L, Lind CL, Miller L, G,Pasterkamp Maegdefessel A, Ruusalepp JR, AV, Priest Eberhard AAC, Newman A, Rao N, P, Tsao Tsantilas AM, Flores KU, Jarr Y, KL, Howe Kojima S, Xiao Ye D, J, V, Y, Direnzo Wang Nanda complement cascade. the activating and efferocytosis atherosclerosis by escaping promote cells muscle Clonally expanding smooth (Epub) 15 June 2020 Sciences of Academy National the of Proceedings KJ. Hasenkrug IL, Weissman KS, T, Lang Adomati JS, Glenn MM, Davis D, Sahoo A, Ahmed DM, J, Monack Rajadas N, Banaei RS, Kalluru D, T, Corey Nguyen BJ, Fram D, Wagh S, P, Galloway TA, Hansen CW, Woods Winkler KE, Peterson M, Hasenkrug M, J, Markovic Kortmann E, Gars RJ, Messer AB, Carmody E, Pham C, Angel Lopez YY, Yiu E, Castro AC, Bohrer KD, Mayer-Barber LB, Cham L, Myers LB, Dulgeroff Tal Torrez MC, pathogen recognition. to response checkpoint host a Is CD47 of Upregulation 23 June 2020 mBio 25

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