| Literature DB >> 25259922 |
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.
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:Entities:
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Year: 2014 PMID： 25259922 PMCID： PMC4177038 DOI： 10.1016/j.cell.2014.08.007
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582