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Title: Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy      
keywords:
Transcriptome or Gene expression
ID:
PRJNA187388
description:
The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) has been attributed to intrinsic resistance to chemotherapy and a growth-permissive tumor microenvironment. Quiescent pancreatic stellate cells (PSCs) are neuroendocrine, nestin-positive, lipid-accumulating cells whose homologues in the liver are the principal repository of Vitamin A esters. Upon activation, lipid droplets are lost and via transdifferentiation they become the key cell type responsible for driving the severe desmoplasia that characterizes PDA. Despite their critical role in PDA progression and chemoresistance, therapeutic strategies targeting PSCs are lacking. Here we identified the vitamin D receptor (VDR) as a master genomic regulator of PSC activation and function. In vitro we demonstrate that VDR activation reduces expression in PSCs of genes implicated in activation, inflammation, and extracellular matrix production, as well as restoring lipid droplet integrity. In vivo, the VDR ligand calcipotriol enhances the anti-tumor effects of gemcitabine by increasing intratumoral concentration 5-fold, reducing tumor volume to near baseline and lowering metastases by more than 65%. These findings implicate VDR as a master regulator of PSC activation and identify a novel therapeutic approach for the treatment of pancreatic cancer. Overall design: RNA-Seq analyses was used to characterize cancer-associated changes between pre-activated (3-day culture) and activated (7-day culture) primary mouse PSCs, as well as control and PDA human PSCs. RNA-Seq was also used to assess the impact of VDR activation (DMSO vs calcipotriol) in a human PSC line (MiaPaCa-2), the mouse primary PSCs
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA187388
authentication:
none
authorization:
none
ID:
pmid:25259922
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • R01 HL105278/HL/NHLBI NIH HHS/United States

  • R24 DK090962/DK/NIDDK NIH HHS/United States

  • CA014195/CA/NCI NIH HHS/United States

  • DK0577978/DK/NIDDK NIH HHS/United States

  • P42 ES010337/ES/NIEHS NIH HHS/United States

  • T32 CA009370/CA/NCI NIH HHS/United States

  • P01 CA163200/CA/NCI NIH HHS/United States

  • Howard Hughes Medical Institute/United States

  • R37 DK057978/DK/NIDDK NIH HHS/United States

  • P30 CA045508/CA/NCI NIH HHS/United States

  • T32 CA148056/CA/NCI NIH HHS/United States

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