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 LauJenny E. Gunton, Geoffrey M. Wahl, Tony Hunter, Jeffrey A. Drebin, Peter J. O'Dwyer, Christopher Liddle, David A. Tuveson, Michael Downes, Ronald M. Evans

Research output: Contribution to journalArticle

441 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)80-93
Number of pages14
JournalCell
Volume159
Issue number1
DOIs
StatePublished - Sep 25 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sherman, M. H., Yu, R. T., Engle, D. D., Ding, N., Atkins, A. R., Tiriac, H., Collisson, E. A., Connor, F., Van Dyke, T., Kozlov, S., Martin, P., Tseng, T. W., Dawson, D. W., Donahue, T. R., Masamune, A., Shimosegawa, T., Apte, M. V., Wilson, J. S., Ng, B., ... Evans, R. M. (2014). Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell, 159(1), 80-93. https://doi.org/10.1016/j.cell.2014.08.007