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Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma.
Chung, Katherine Minjee; Singh, Jaffarguriqbal; Lawres, Lauren; Dorans, Kimberly Judith; Garcia, Cathy; Burkhardt, Daniel B; Robbins, Rebecca; Bhutkar, Arjun; Cardone, Rebecca; Zhao, Xiaojian; Babic, Ana; Vayrynen, Sara A; Dias Costa, Andressa; Nowak, Jonathan A; Chang, Daniel T; Dunne, Richard F; Hezel, Aram F; Koong, Albert C; Wilhelm, Joshua J; Bellin, Melena D; Nylander, Vibe; Gloyn, Anna L; McCarthy, Mark I; Kibbey, Richard G; Krishnaswamy, Smita; Wolpin, Brian M; Jacks, Tyler; Fuchs, Charles S; Muzumdar, Mandar Deepak.
Afiliação
  • Chung KM; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
  • Singh J; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
  • Lawres L; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
  • Dorans KJ; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
  • Garcia C; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
  • Burkhardt DB; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Robbins R; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
  • Bhutkar A; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
  • Cardone R; Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Zhao X; Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Babic A; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA.
  • Vayrynen SA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA.
  • Dias Costa A; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA.
  • Nowak JA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Chang DT; Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA 94305, USA.
  • Dunne RF; Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14627, USA.
  • Hezel AF; Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14627, USA.
  • Koong AC; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wilhelm JJ; Schulze Diabetes Institute and Department of Surgery, University of Minnesota Medical Center, Minneapolis, MN 55454, USA.
  • Bellin MD; Schulze Diabetes Institute and Department of Surgery, University of Minnesota Medical Center, Minneapolis, MN 55454, USA; Department of Pediatrics, University of Minnesota Medical Center, Minneapolis, MN 55454, USA.
  • Nylander V; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
  • Gloyn AL; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Oxford NIHR Biomedical Research Centre, Oxford Universi
  • McCarthy MI; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Oxford NIHR Biomedical Research Centre, Oxford Universi
  • Kibbey RG; Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Krishnaswamy S; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Wolpin BM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA.
  • Jacks T; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Fuchs CS; Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT 06511, USA.
  • Muzumdar MD; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT 06511, USA. Electronic address: mandar.muzumdar@yale.edu.
Cell ; 181(4): 832-847.e18, 2020 05 14.
Article em En | MEDLINE | ID: mdl-32304665
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma Ductal Pancreático / Obesidade Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma Ductal Pancreático / Obesidade Idioma: En Ano de publicação: 2020 Tipo de documento: Article