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Loss of microRNA ‐21 leads to profound stromal remodeling and short survival in K‐Ras ‐driven mouse models of pancreatic cancer
Author(s) -
Schipper Josh,
Westerhuis Jennifer J.,
Beddows Ian,
Madaj Zach,
Monsma David,
Hostetter Galen,
Kiupel Matti,
ConejoGarcia Jose R.,
Sempere Lorenzo F.
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33041
Subject(s) - cancer research , stromal cell , biology , pancreatic cancer , tumor microenvironment , cancer , desmoplasia , tumor progression , cancer associated fibroblasts , microrna , reprogramming , adenocarcinoma , tumor initiation , immune system , gene signature , cell , carcinogenesis , immunology , gene expression , gene , genetics
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.