Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy

Sherman, Mara H, Yu, Ruth T, Engle, Dannielle D, Ding, Ning, Atkins, Annette R, Tiriac, Herve, Collisson, Eric A, Connor, Frances, Van Dyke, Terry, Kozlov, Serguei, Martin, Philip, Tseng, Tiffany W, Dawson, David W, Donahue, Timothy R, Masamune, Atsushi, Shimosegawa, Tooru, Apte, Minoti V, Wilson, Jeremy S, Ng, Beverly, Lau, Sue Lynn, Gunton, Jenny E, Wahl, Geoffrey M, Hunter, Tony, Drebin, Jeffrey A, O’Dwyer, Peter J, Liddle, Christopher, Tuveson, David A, Downes, Michael, Evans, Ronald M (2014) Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy. Cell, 159 (1). pp. 80-93. ISSN 0092-8674

URL: http://www.ncbi.nlm.nih.gov/pubmed/25259922
DOI: 10.1016/j.cell.2014.08.007

Abstract

Summary 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > pancreatic cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Vitamin D receptor
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL labs > Tuveson lab
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
Depositing User: Matt Covey
Date Deposited: 03 Oct 2014 15:25
Last Modified: 29 Oct 2015 20:43
PMCID: PMC4177038
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30825

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