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

Autor: Schipper J; Van Andel Research Institute, Grand Rapids, Michigan, USA., Westerhuis JJ; Van Andel Research Institute, Grand Rapids, Michigan, USA., Beddows I; Van Andel Research Institute, Grand Rapids, Michigan, USA., Madaj Z; Van Andel Research Institute, Grand Rapids, Michigan, USA., Monsma D; Van Andel Research Institute, Grand Rapids, Michigan, USA., Hostetter G; Van Andel Research Institute, Grand Rapids, Michigan, USA., Kiupel M; Veterinary Diagnostic Laboratory, Michigan State University, Lansing, Michigan, USA., Conejo-Garcia JR; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA., Sempere LF; Precision Health Program, Michigan State University, East Lansing, Michigan, USA.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2020 Oct 15; Vol. 147 (8), pp. 2265-2278. Date of Electronic Publication: 2020 May 26.
DOI: 10.1002/ijc.33041
Abstrakt: 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.
(© 2020 UICC.)
Databáze: MEDLINE
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