Loss of microRNA-21 leads to profound stromal remodeling and short survival in K-Ras-driven mouse models of pancreatic cancer.

Abstract

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 profibrotic noncoding 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 The Cancer Genome Atlas 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 to remodel the tumor microenvironment and enhance treatment response in PDAC.

• Authors: Josh Schipper, Jennifer J Westerhuis, Ian Beddows, Zach Madaj, David Monsma, Galen Hostetter, Matti Kiupel, Jose R Conejo-Garcia, Lorenzo F Sempere
• Journal: International journal of cancer (Int J Cancer) Vol. 147 Issue 8 Pg. 2265-2278 (10 15 2020) ISSN: 1097-0215 [Electronic] United States
• PMID: 32388866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 UICC.

Chemical References

• MIRN21 microRNA, human
• MicroRNAs
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Disease Models, Animal
• Female
• Fibroblasts (pathology)
• Gene Expression Regulation, Neoplastic (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs (genetics)
• Pancreatic Neoplasms (genetics, pathology)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Transcriptome (genetics)
• Tumor Microenvironment (genetics)
• Pancreatic Neoplasms