title: Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.
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:
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Mara H
authors.initials: MH
authors.lastname: Sherman
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Dannielle D
authors.initials: DD
authors.lastname: Engle
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Herve
authors.initials: H
authors.lastname: Tiriac
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.affiliation: Cancer Research UK Cambridge Research Institute, The Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Connor
authors.affiliation: Center for Advanced Preclinical Research, NCI-Frederick, Frederick, MD 21702, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomed, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomed, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Martin
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Tiffany W
authors.initials: TW
authors.lastname: Tseng
authors.affiliation: Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai Miyagi, 980-8574, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai Miyagi, 980-8574, Japan.
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.affiliation: Pancreatic Research Group, Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Minoti V
authors.initials: MV
authors.lastname: Apte
authors.affiliation: Pancreatic Research Group, Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Wilson
authors.affiliation: 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.
authors.forename: Beverly
authors.initials: B
authors.lastname: Ng
authors.affiliation: 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.
authors.forename: Sue Lynn
authors.initials: SL
authors.lastname: Lau
authors.affiliation: 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.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gunton
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Wahl
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.affiliation: Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Drebin
authors.affiliation: Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.affiliation: The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: 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.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy / Q000517:prevention & control; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; C055085:calcipotriene; D002117:Calcitriol