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| Status |
Public on Oct 03, 2014 |
| Title |
Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
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| 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
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| Contributor(s) |
Yu RT, Sherman MH, Evans RM |
| Citation(s) |
25259922 |
| Submission date |
Jan 25, 2013 |
| Last update date |
May 15, 2019 |
| Contact name |
Ruth T Yu |
| Organization name |
Salk Institute
|
| Department |
Gene Expression Lab
|
| Lab |
Ronald Evans
|
| Street address |
10010 N Torrey Pines Rd
|
| City |
La Jolla |
| State/province |
CA |
| ZIP/Postal code |
92037 |
| Country |
USA |
| |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
|
| Samples (17)
|
| GSM1070768 |
PSC from PDA patient [CA7] |
| GSM1070769 |
PSC from non-cancer control [DI1] |
| GSM1070770 |
PSC from non-cancer control [DI2] |
| GSM1070771 |
PSC from non-cancer control [DI3] |
| GSM1070772 |
PSC from non-cancer control [DI4] |
| GSM1070773 |
PSC from non-cancer control [DI5] |
| GSM1070774 |
MiaPaCa-2 cells treated with DMEM [Mia-DMEM] |
| GSM1070775 |
MiaPaCa-2 cells treated with calcipotriol [Mia-CAL] |
| GSM1070776 |
MiaPaCa-2 cells treated with conditioned media [Mia-CM] |
| GSM1070777 |
MiaPaCa-2 cells treated with conditioned media [Mia-CMS] |
| GSM1070778 |
day 3 mouse PSCs treated with DMEM [mPSC-d3] |
| GSM1070779 |
day 3 mouse PSCs treated with calcipotriol [mPSC-d3-CAL] |
| GSM1070780 |
day 7 mouse PSCs treated with DMEM [mPSC-d7] |
| GSM1070781 |
day 7 mouse PSCs treated with calcipotriol [mPSC-d7-CAL] |
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| Relations |
| SRA |
SRP018218 |
| BioProject |
PRJNA187388 |
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