Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma

Katherine Minjee Chung, Jaffarguriqbal Singh, Lauren Lawres, Kimberly Judith Dorans, Cathy Garcia, Daniel B. Burkhardt, Rebecca Robbins, Arjun Bhutkar, Rebecca Cardone, Xiaojian Zhao, Ana Babic, Sara A. Vayrynen, Andressa Dias Costa, Jonathan A. Nowak, Daniel T. Chang, Richard F. Dunne, Aram F. Hezel, Albert C. Koong, Joshua J. Wilhelm, Melena D. BellinVibe Nylander, Anna L. Gloyn, Mark I. McCarthy, Richard G. Kibbey, Smita Krishnaswamy, Brian M. Wolpin, Tyler Jacks, Charles S. Fuchs, Mandar Deepak Muzumdar

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.

Original languageEnglish (US)
Pages (from-to)832-847.e18
JournalCell
Volume181
Issue number4
DOIs
StatePublished - May 14 2020

Bibliographical note

Funding Information:
This work was supported in part by a Lustgarten Foundation Research Investigator Grant (to C.S.F. and M.D.M.); Cancer Center Support (core) grants ( P30-CA016359 to C.S.F. and P30-CA014051 to T.J.) from the NCI ; a Pilot Grant from the Yale Cancer Center (to M.D.M.); a Yale Cancer Innovations Award (to M.D.M.); and an NIH Director’s New Innovator Award ( DP2-CA248136 to M.D.M.). The National Institute for Health Research, Oxford Biomedical Research Centre funded islet provision. C.G. is funded by the NIH/NIGMS ( T32-GM007499 ). D.B.B. is funded by the NICHD ( F31-HD097958 ). A.B. is funded by the NCI ( K07-CA222159 ) and a Bob Parsons Fellowship. A.L.G. received support as a Wellcome Senior Fellow in Basic Biomedical Science with funding in Oxford by the Wellcome Trust ( 095101 , 200837 , 106130 , and 203141 ), the Medical Research Council ( MR/L020149/1 ), the European Union Horizon 2020 Programme (T2D Systems), and the NIDDK ( U01-DK105535 and U01-DK085545 ). M.I.M. received support as a Wellcome Senior Investigator and an NIHR Senior Investigator. Relevant funding support for this work came from Wellcome ( 090532 , 098381 , and 212259 ) and the NIHR ( NF-SI-0617-10090 ). The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. R.G.K. is funded by the NIDDK ( P30-DK045735 and R01-DK110181 ) and a Yale Cancer Innovations Award . S.K. is funded by the NIH ( R01-GM130847 ), HIPC ( 2U19AI089992 ), and Chan Zuckerberg Initiative ( CZF2019-002440 ). B.M.W. acknowledges support from the Hale Family Center for Pancreatic Cancer Research , Lustgarten Foundation , NIH ( U01-CA210171 ), Stand Up To Cancer , Noble Effort Fund , Wexler Family Fund , and Promises for Purple . T.J. is a Howard Hughes Medical Institute Investigator , the David H. Koch Professor of Biology , and a Daniel K. Ludwig Scholar . M.D.M. is supported by the NCI ( K08-CA2080016 ) and was supported by a Conquer Cancer Foundation-American Society for Clinical Oncology (CCF-ASCO) Young Investigator Award and the NIH Loan Repayment Program . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
We thank F. Gorelick, M. Lemmon, and F. Wilson for critical reading of the manuscript; K. Mercer for technical assistance; K. Cormier and C. Condon from the Hope Babette Tang (1983) Histology Facility of the Koch Institute Swanson Biotechnology Center; A. Brooks, P. Gaule, Y. Bai, B. Acs, and D. Rhim from Yale Pathology Tissue Services for histology assistance; M. Robert and R. Bronson for pathology assistance; S. Levine, V. Dayal, and J. Penterman from the MIT BioMicro Center for bulk RNA-seq support; J. Heitke, G. Wang, C. Castaldi, and S. Mane from the Yale Center for Genome Analysis for assisting with scRNA-seq; the University of Iowa Viral Vector core for AAV constructs and generation; M. Batsu and R. Jacobs from the Yale Diabetes Research Core for serum ELISA/RIA studies; the Oxford Human Islet Isolation facility for the provision of human islets for research; T. Kolodecik and F. Gorelick for providing murine pancreatitis specimens; F. Zheng for CRISPR constructs; and A. Berns, D.B. Davis, A. Lowy, L. Luo, and Jackson Laboratories for mice. This work was supported in part by a Lustgarten Foundation Research Investigator Grant (to C.S.F. and M.D.M.); Cancer Center Support (core) grants (P30-CA016359 to C.S.F. and P30-CA014051 to T.J.) from the NCI; a Pilot Grant from the Yale Cancer Center (to M.D.M.); a Yale Cancer Innovations Award (to M.D.M.); and an NIH Director's New Innovator Award (DP2-CA248136 to M.D.M.). The National Institute for Health Research, Oxford Biomedical Research Centre funded islet provision. C.G. is funded by the NIH/NIGMS (T32-GM007499). D.B.B. is funded by the NICHD (F31-HD097958). A.B. is funded by the NCI (K07-CA222159) and a Bob Parsons Fellowship. A.L.G. received support as a Wellcome Senior Fellow in Basic Biomedical Science with funding in Oxford by the Wellcome Trust (095101, 200837, 106130, and 203141), the Medical Research Council (MR/L020149/1), the European Union Horizon 2020 Programme (T2D Systems), and the NIDDK (U01-DK105535 and U01-DK085545). M.I.M. received support as a Wellcome Senior Investigator and an NIHR Senior Investigator. Relevant funding support for this work came from Wellcome (090532, 098381, and 212259) and the NIHR (NF-SI-0617-10090). The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. R.G.K. is funded by the NIDDK (P30-DK045735 and R01-DK110181) and a Yale Cancer Innovations Award. S.K. is funded by the NIH (R01-GM130847), HIPC (2U19AI089992), and Chan Zuckerberg Initiative (CZF2019-002440). B.M.W. acknowledges support from the Hale Family Center for Pancreatic Cancer Research, Lustgarten Foundation, NIH (U01-CA210171), Stand Up To Cancer, Noble Effort Fund, Wexler Family Fund, and Promises for Purple. T.J. is a Howard Hughes Medical Institute Investigator, the David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar. M.D.M. is supported by the NCI (K08-CA2080016) and was supported by a Conquer Cancer Foundation-American Society for Clinical Oncology (CCF-ASCO) Young Investigator Award and the NIH Loan Repayment Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. T.J. C.S.F. and M.D.M. designed and supervised the study; K.M.C. J.S. L.L. K.J.D. C.G. R.R. and M.D.M. performed experiments; D.B.B. and S.K. conducted scRNA-seq computational analyses; A.B. conducted exome computational analyses and bulk RNA-seq expression signature analyses; R.C. X.Z. and R.G.K. performed and analyzed islet isolation and perifusion studies; A.B. J.N. S.A.V. A.D.C. and B.M.W. performed targeted exome and IHC analyses on human PDAC; D.T.C. R.F.D. A.F.H. A.C.K. J.J.W. and M.D.B. provided human PDAC and pancreatitis biospecimens; V.N. A.L.G. and M.I.M. acquired and analyzed human donor islet gene expression data; M.D.M. wrote the manuscript with comments from all authors. K.J.D. is currently an employee of Sherlock Biosciences. M.D.B. acknowledges research support from ViaCyte and Dexcom and serves on the medical advisory boards for Novo Nordisk and ARIEL Precision Medicine. A.L.G. has received honoraria from Merck and Novo Nordisk and has received research funding from Novo Nordisk. M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; he has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. R.G.K. is co-founder and a Scientific Advisory Board member of Elucidata; a Consultant/Advisory Board member for Agios, Janssen, BI-Lilly, and Pfizer; and a recipient of sponsored research agreements from Agios, AstraZeneca/BMS, Lilly, Pfizer, and Poxel. S.K. is a paid scientific advisor to AI Therapeutics. B.M.W. declares research funding from Celgene and Eli Lilly & Company, and consults for BioLineRx, Celgene, G1 Therapeutics, and GRAIL. T.J. is a Board of Directors member of Amgen and Thermo Fisher Scientific, co-founder and Scientific Advisory Board member of Dragonfly Therapeutics, co-founder of T2 Biosystems, and Scientific Advisory Board member of SQZ Biotech with equity holding in all five companies; he receives funding from the Johnson & Johnson Lung Cancer Initiative and Calico. C.S.F. reports receiving personal fees from Eli Lilly, Entrinsic Health, Pfizer, Merck, Sanofi, Roche, Genentech, Merrimack Pharma, Dicerna, Bayer, Celgene, Agios, Gilead Sciences, Five Prime Therapeutics, Taiho, KEW, and CytomX Therapeutics and receiving support from CytomX Therapeutics. M.D.M. acknowledges research support from Genentech.

Funding Information:
K.J.D. is currently an employee of Sherlock Biosciences. M.D.B. acknowledges research support from ViaCyte and Dexcom and serves on the medical advisory boards for Novo Nordisk and ARIEL Precision Medicine. A.L.G. has received honoraria from Merck and Novo Nordisk and has received research funding from Novo Nordisk. M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; he has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. R.G.K. is co-founder and a Scientific Advisory Board member of Elucidata; a Consultant/Advisory Board member for Agios, Janssen, BI-Lilly, and Pfizer; and a recipient of sponsored research agreements from Agios, AstraZeneca/BMS, Lilly, Pfizer, and Poxel. S.K. is a paid scientific advisor to AI Therapeutics. B.M.W. declares research funding from Celgene and Eli Lilly & Company, and consults for BioLineRx, Celgene, G1 Therapeutics, and GRAIL. T.J. is a Board of Directors member of Amgen and Thermo Fisher Scientific, co-founder and Scientific Advisory Board member of Dragonfly Therapeutics, co-founder of T2 Biosystems, and Scientific Advisory Board member of SQZ Biotech with equity holding in all five companies; he receives funding from the Johnson & Johnson Lung Cancer Initiative and Calico. C.S.F. reports receiving personal fees from Eli Lilly, Entrinsic Health, Pfizer, Merck, Sanofi, Roche, Genentech, Merrimack Pharma, Dicerna, Bayer, Celgene, Agios, Gilead Sciences, Five Prime Therapeutics, Taiho, KEW, and CytomX Therapeutics and receiving support from CytomX Therapeutics. M.D.M. acknowledges research support from Genentech.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • beta cells
  • cholecystokinin
  • genetically engineered mouse models
  • leptin
  • obesity
  • pancreatic cancer
  • pancreatic islets
  • tumor microenvironment
  • Carcinoma, Pancreatic Ductal/etiology
  • Humans
  • Male
  • Pancreatic Neoplasms/metabolism
  • Endocrine Cells/metabolism
  • Obesity/genetics
  • Exocrine Glands/metabolism
  • Tumor Microenvironment/physiology
  • Female
  • Gene Expression Regulation, Neoplastic/genetics
  • Disease Models, Animal
  • Cell Line
  • Mutation/genetics
  • Mice, Inbred C57BL
  • Signal Transduction/genetics
  • Cell Transformation, Neoplastic/genetics
  • Disease Progression
  • Animals
  • Cell Line, Tumor
  • Mice
  • Carcinogenesis/genetics

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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