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| Status |
Public on May 05, 2020 |
| Title |
Loss of microRNA-21 in K-Ras-driven mouse models of pancreatic cancer |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor-restraining and tumor-promoting fibroblast subpopulations. Re-education rather than indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied the effects of global loss of pro-fibrotic non-coding regulatory microRNA-21 (miR-21) in K-Ras-driven p53-deleted genetically engineered mouse models of PDAC. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. The absence of tumor-restraining myofibroblasts and a massive infiltrate of immune cells were salient phenotypic features of global miR-21 loss. Stromal miR-21 activity was required for induction of tumor-restraining myofibroblasts in in-vivo isograft transplantation experiments. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in TCGA PDAC data set (n = 156) mirroring findings in the mouse models. Our results exposed an overall tumor suppressive function of miR-21 in in-vivo PDAC models. These results have important clinical implications for anti-miR-21-based inhibitory therapeutic approaches under consideration for PDAC and other cancer types. Mechanistic dissection of the cell-intrinsic role of miR-21 in cancer-associated fibroblasts and other cell types will be needed to inform best strategies for pharmacological modulation of miR-21 activity in order to remodel the tumor microenvironment and enhance treatment response in PDAC.
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| Overall design |
Twenty two samples derived from Bl6 mouse tumor (n=12) and a pancreatic cell line (n=10). For both tumor and cell line, there are WT and miR21-KO samples.
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| Contributor(s) |
Sempere LF, Schipper J, Beddows I |
| Citation(s) |
32388866 |
| |
| Submission date |
Oct 11, 2019 |
| Last update date |
Jun 03, 2020 |
| Contact name |
Ian Beddows |
| E-mail(s) |
ian.beddows@vai.org
|
| Organization name |
Van Andel Institute
|
| Street address |
333 Bostwick Ave NE
|
| City |
Grand Rapids |
| State/province |
MI |
| ZIP/Postal code |
49503 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (22)
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| Relations |
| BioProject |
PRJNA577106 |
| SRA |
SRP225208 |
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