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 (September 2014) Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy. Cell, 159 (1). pp. 80-93. ISSN 0092-8674
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: | 25 September 2014 |
| Date Deposited: | 03 Oct 2014 15:25 |
| Last Modified: | 29 Oct 2015 20:43 |
| PMCID: | PMC4177038 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30825 |
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