Abstract A48: Genetic ablation of microRNA-21 profoundly remodels stroma and shortens survival of K-Ras-driven pancreatic cancer mouse models

Abstract

The tumor 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 global loss of profibrotic noncoding regulatory microRNA-21 (miR-21) in K-Ras-driven genetically engineered mouse models of PDAC. We generated mouse strains carrying wild-type or knockout alleles of Mir-21 in a well-characterized K-Ras-driven, p53-deleted PDAC model (LSL-KrasG12D; p53lox/+;Pdx1-Cre, KPC). Even though miR-21 expression was upregulated in cancer cells and cancer-associated fibroblasts in KPC tumors, global loss of miR-21 activity did not inhibit tumor growth. 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. We uncovered a cell-autonomous requirement of miR-21 activity for induction of tumor-restraining myofibroblasts, whose absence led to a profound remodeling of the stroma and massive infiltrate of tumor-permissive immune cells. 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 genetic models. In vitro and in vivo isograft experiments showed that miR-21 activity was dispensable for cancer cell growth but required for complete execution of TGF-b-mediated programs. Our results suggest that modulation of miR-21 activity may provide a novel therapeutic opportunity to affect the composition of fibroblast subpopulations and enhance current chemotherapy and/or immunotherapy treatments. Citation Format: Josh Schipper, Ian Beddows, Matti Kiupel, Jose Conejo-Garcia, Lorenzo Sempere. Genetic ablation of microRNA-21 profoundly remodels stroma and shortens survival of K-Ras-driven pancreatic cancer mouse models [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A48.