Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

Mara H Sherman; Ruth T Yu; Dannielle D Engle; Ning Ding; Annette R Atkins; Herve Tiriac; Eric A Collisson; Frances Connor; Terry Van Dyke; Serguei Kozlov; Philip Martin; Tiffany W Tseng; David W Dawson; Timothy R Donahue; Atsushi Masamune; Tooru Shimosegawa; Minoti V Apte; Jeremy S Wilson; Beverly Ng; Sue Lynn Lau; Jenny E Gunton; Geoffrey M Wahl; Tony Hunter; Jeffrey A Drebin; Peter J O'Dwyer; Christopher Liddle; David A Tuveson; Michael Downes; Ronald M Evans

doi:10.1016/j.cell.2014.08.007

Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

Cell. 2014 Sep 25;159(1):80-93. doi: 10.1016/j.cell.2014.08.007.

Authors

Mara H Sherman¹, Ruth T Yu¹, Dannielle D Engle², Ning Ding¹, Annette R Atkins¹, Herve Tiriac², Eric A Collisson³, Frances Connor⁴, Terry Van Dyke⁵, Serguei Kozlov⁶, Philip Martin⁶, Tiffany W Tseng¹, David W Dawson⁷, Timothy R Donahue⁷, Atsushi Masamune⁸, Tooru Shimosegawa⁸, Minoti V Apte⁹, Jeremy S Wilson⁹, Beverly Ng¹⁰, Sue Lynn Lau¹¹, Jenny E Gunton¹², Geoffrey M Wahl¹, Tony Hunter¹³, Jeffrey A Drebin¹⁴, Peter J O'Dwyer¹⁵, Christopher Liddle¹⁶, David A Tuveson², Michael Downes¹⁷, Ronald M Evans¹⁸

Affiliations

¹ Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.
² Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
³ Department of Medicine/Hematology and Oncology, University of California San Francisco, San Francisco, CA 94143, USA.
⁴ Cancer Research UK Cambridge Research Institute, The Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.
⁵ Center for Advanced Preclinical Research, NCI-Frederick, Frederick, MD 21702, USA.
⁶ Center for Advanced Preclinical Research, Leidos Biomed, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁷ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai Miyagi, 980-8574, Japan.
⁹ Pancreatic Research Group, Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
¹⁰ Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
¹¹ Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, NSW 2010, Australia; Faculty of Medicine, University of Sydney, Sydney, NSW 2052, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW 2145, Australia.
¹² Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia; Faculty of Medicine, University of Sydney, Sydney, NSW 2052, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW 2145, Australia.
¹³ Molecular and Cell Biology Laboratory, Salk Institute, La Jolla, CA 92037, USA.
¹⁴ Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁵ Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
¹⁶ The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
¹⁷ Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu.
¹⁸ Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu.

Abstract

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:

Publication types

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

MeSH terms

Adenocarcinoma / drug therapy*
Adenocarcinoma / pathology
Animals
Antineoplastic Agents / pharmacology*
Calcitriol / analogs & derivatives*
Calcitriol / pharmacology
Carcinoma, Pancreatic Ductal / drug therapy*
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Disease Models, Animal
Gene Expression Profiling
Humans
Mice, Inbred C57BL
Molecular Sequence Data
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / pathology
Pancreatitis / drug therapy
Pancreatitis / prevention & control
Receptors, Calcitriol / metabolism*
Signal Transduction
Stromal Cells / pathology

Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

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