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YAP–IL-6ST Autoregulatory Loop Activated on APC Loss Controls Colonic Tumorigenesis

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YAP–IL-6ST Autoregulatory Loop Activated on APC Loss Controls Colonic Tumorigenesis YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis Koji Taniguchia,b,c,d,e, Toshiro Moroishif, Petrus R. de Jongg,h, Michal Krawczyki, Britta Moyo Grebbinj,k,l, Huiyan Luoi,m, Rui-hua Xum, Nicole Golob-Schwarzln, Caroline Schweigern, Kepeng Wanga,b,c,o, Giuseppe Di Caroa,b,c, Ying Fengp, Eric R. Fearonp,q,r, Eyal Razg, Lukas Kenners,t,u, Henner F. Farinj,k,l, Kun-Liang Guanf, Johannes Haybaeckn,v, Christian Datzw, Kang Zhangi, and Michael Karina,b,c,x,1 aLaboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, CA 92093; bDepartment of Pharmacology, University of California, San Diego, La Jolla, CA 92093; cDepartment of Pathology, University of California, San Diego, La Jolla, CA 92093; dDepartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; eDepartment of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; fDepartment of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093; gDepartment of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093; hSanford Burnham Prebys Medical Discovery Institute, National Cancer Institute-Designated Cancer Center, La Jolla, CA 92037; iInstitute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093; jGerman Cancer Consortium, 69120 Heidelberg, Germany; kGeorg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt on Main, Germany; lGerman Cancer Research Center, 69120 Heidelberg, Germany; mState Key Laboratory of Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China; nInstitute of Pathology, Medical University of Graz, Graz A-8036, Austria; oDepartment of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, 06030; pDepartment of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; qDepartment of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109; rDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; sClinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria; tLudwig Boltzmann Institute for Cancer Research, Medical University of Vienna, 1090 Vienna, Austria; uDepartment for Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; vDepartment of Pathology, Otto-von-Guericke University of Magdeburg, 39120 Magdeburg, Germany; wDepartment of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, 5110 Oberndorf, Austria; and xMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093 Contributed by Michael Karin, December 12, 2016 (sent for review November 17, 2016; reviewed by Matthias Ernst and Stefan Rose-John) Loss of tumor suppressor adenomatous polyposis coli (APC) 3-kinase (PI3K) signaling mediate malignant progression (9). So far, activates β-catenin to initiate colorectal tumorigenesis. However, however, MAPK and PI3K inhibition had only a marginal impact β-catenin (CTNNB1) activating mutations rarely occur in human on survival in advanced CRC patients (10) and restoration of APC, MEDICAL SCIENCES colorectal cancer (CRC). We found that APC loss also results in p53, and TGF-β tumor suppressor activity remains an elusive goal. up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby CRC pathogenesis is enhanced by inflammation (11). In the activating Src family kinases (SFKs), YAP, and STAT3, which are case of inflammatory bowel diseases, which greatly increase CRC simultaneously up-regulated in the majority of human CRC. Al- risk, inflammation is caused by autoimmunity (12). However, though, initial YAP activation, which stimulates IL6ST gene tran- even sporadic CRC, initiated by APC loss, depends on “tumor- scription, may be caused by reduced serine phosphorylation, elicited inflammation,” which originates from localized loss of the sustained YAP activation depends on tyrosine phosphorylation intestinal epithelial barrier (13). Barrier disruption results in in- by SFKs, whose inhibition, along with STAT3-activating JAK ki- vasion of early benign tumors (adenomas) by components of the nases, causes regression of established colorectal tumors. These – APC colonic microbiota, which activate IL-23 synthesizing myeloid cells results explain why loss is a more potent initiating event than and expand tumor-resident IL-17–producing T lymphocytes (13). the mere activation of CTNNB1. colorectal cancer | adenomatous polyposis coli | IL-6ST/gp130 | YAP | STAT3 Significance Current therapy for advanced colorectal cancer (CRC) is un- olorectal cancer (CRC) is the fourth leading cause of cancer- satisfactory and CRC remains a major cause of cancer-related related deaths in males and third in females (1). Although C deaths. Thus, novel and ubiquitously acting oncogenic mediators early CRC (stages I and II) can be controlled by surgical re- that are amenable to pharmacological targeting need to be iden- section accompanied by chemotherapy, advanced CRC (stages tified. We found that loss of adenomatous polyposis coli (APC), III and IV) is associated with high mortality rates (2). In such which is mutated in the majority of human CRC, results in up-reg- patients, targeted therapies, including EGF receptor and an- ulation of the signaling protein IL-6ST/gp130. This results in acti- giogenesis inhibitors, prolong survival only by several months (3). vation of Src family kinases (SFKs),YAP,Notch,andSTAT3,which Furthermore, only a small fraction of CRC patients, whose tu- are simultaneously activated in 64% of human CRC. In addition to mors are mismatch repair-deficient, respond positively to im- better explaining how APC loss initiates colorectal tumorigenesis, munotherapy (4). Undoubtedly, the future of CRC therapy we show that combined treatment withSFKandJAKinhibitors depends on identification of novel and ubiquitously acting on- results in regression of established colorectal tumors in mice. cogenic mediators whose targeting will cause tumor regression in most patients. Author contributions: K.T. and M. Karin designed research; K.T., T.M., P.R.d.J., B.M.G., CRC pathogenesis often follows a well-defined multistep K.W., G.D.C., E.R., H.F.F., and K.-L.G. performed research; K.T., M. Krawczyk, H.L., R.-h.X., genetic pathway that leads to sequential activation of several N.G.-S., C.S., Y.F., E.R.F., L.K., J.H., C.D., and K.Z. contributed new reagents/analytic tools; key signal transducers and transcription factors (5, 6). The most K.T., T.M., P.R.d.J., B.M.G., K.W., G.D.C., E.R., H.F.F., K.-L.G., and M. Karin analyzed data; frequent tumor-initiating event is inactivation of the adeno- and K.T. and M. Karin wrote the paper. matous polyposis coli (APC) tumor suppressor, resulting in Reviewers: M.E., Olivia Newton-John Cancer Research Institute; and S.R.-J., Christian- stabilization and irreversible activation of β-catenin (CTNNB1) Albrechts-Universität zu Kiel. (7). The much higher frequency of APC loss-of-function mu- K.-L.G. is a co-founder and has an equity interest in Vivace Therapeutics, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San tations relative to CTNNB1 gain-of-function mutations (8) Diego, in accordance with its conflict of interest policies. The other authors declare no suggests that APC loss leads to activation of at least one more conflict of interest. oncogenic pathway that remains to be identified. Subsequent 1To whom correspondence should be addressed. Email: [email protected]. β mutations that disrupt the tumor suppressive p53 and TGF- path- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. way and activate Ras-MAP kinase (MAPK) and phosphoinositide 1073/pnas.1620290114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1620290114 PNAS Early Edition | 1of6 Downloaded by guest on September 30, 2021 (12). To query their involvement in colorectal tumorigenesis, we A P-Src YAP P-STAT3 HES1 stained a collection of human CRC surgical specimens (n = 17) with antibodies to phosphorylated Src and STAT3, YAP, and Non- HES1, a Notch target. Strikingly, 59% of the tumors exhibited Tumor concomitant activation and up-regulation of all four signaling molecules relative to nontumor tissue (Fig. 1A, Fig. S1A, and Table S1). Analysis of mouse colon tumors induced by APC loss Tumor revealed an identical scenario: concomitant Src, STAT3, YAP, and Notch activation in tumor specimens (Fig. 1B). We further confirmed and extended the human data using another cohort of B human colon tissue microarrays (TMA). Approximately 67% of P-Src YAP P-STAT3 HES1 these CRC specimens (n = 27) were positive for all four markers, none of which were strongly expressed in normal tissue (Fig. S1 Normal B and C and Table S2). Positivity of all four markers tended to be colon higher at advanced disease stages (Fig. S1D). APC Loss Results in Src, YAP, Notch, and STAT3 Activation. APC in- activation is the most common initiating event in human CRC Tumor development (22), which in addition to β-catenin stabilization (x20) was found to activate YAP through an ill-defined mechanism (23, 24). To examine whether APC loss is responsible for STAT3, SFK, YAP, and Notch activation, we established WT −/− Tumor and Apc mouse small intestinal (SI) organoids (enteroids) by F/F (x10) transducing Apc organoids with Adeno-Cre virus. APC-null enteroids exhibited increased STAT3 and Src tyrosine (Y) phosphorylation (Fig. 2A). YAP expression and Y phosphory- Fig. 1. Multiple gp130-responsive signaling pathways are activated in hu- lation were also up-regulated, along with mRNAs encoding YAP man and mouse colorectal cancer. (A) Paraffin-embedded sections of surgi- targets, connective tissue growth factor (Ctgf) and Cyr61, and the = = − − cally removed human CRC (n 17) and matched normal colon tissues (n 7) Notch ligand Jag1 (Fig. 2 A and B). Apc / organoids exhibited were stained with P-Src, YAP, P-STAT3, or HES1 antibodies.
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