@article{9f3a7f7d620149e38e7874260d33e6b4,
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.",
author = "Sherman, {Mara H.} and Yu, {Ruth T.} and Engle, {Dannielle D.} and Ning Ding and Atkins, {Annette R.} and Herve Tiriac and Collisson, {Eric A.} and Frances Connor and {Van Dyke}, Terry and Serguei Kozlov and Philip Martin and Tseng, {Tiffany W.} and Dawson, {David W.} and Donahue, {Timothy R.} and Atsushi Masamune and Tooru Shimosegawa and Apte, {Minoti V.} and Wilson, {Jeremy S.} and Beverly Ng and Lau, {Sue Lynn} and Gunton, {Jenny E.} and Wahl, {Geoffrey M.} and Tony Hunter and Drebin, {Jeffrey A.} and O'Dwyer, {Peter J.} and Christopher Liddle and Tuveson, {David A.} and Michael Downes and Evans, {Ronald M.}",
note = "Funding Information: We thank E. Ong and C. Brondos for administrative support; M. Baran, T. Guerin, J. Schlomer, J. Kalen, L. Riffel, P. Mackin, S. Kaufman, J. Alvarez, and H. Juguilon for technical assistance; and D. von Hoff and T. Bapiro for discussion. We thank T. Guerin and J. Schlomer for efficacy studies done at the Center for Advanced Preclinical Research (CAPR), the Center for Cancer Research, the National Cancer Institute. M.H.S. was supported by a Ruth L. Kirchstein National Research Service Award (T32-CA009370). This work was funded by grants from the NIH (HL105278, DK0577978, DK090962, CA014195, and ES010337), the Helmsley Charitable Trust, and the Samuel Waxman Cancer Research Foundation. R.M.E. and M.D. are supported in part by a Stand Up to Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0509). C.L. and M.D. are funded by grants from the National Health and Medical Research Council of Australia Project Grants 512354, 632886 and 1043199. M.A. and J.W. are funded by grants from the Cancer Council of NSW. A.M. is supported by Grant-in-Aid from Japan Society for the Promotion of Science (23591008). R.M.E. is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute and supported by a grant from The Lustgarten Foundation. Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",
year = "2014",
month = sep,
day = "25",
doi = "10.1016/j.cell.2014.08.007",
language = "English (US)",
volume = "159",
pages = "80--93",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}