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Re\u2010education 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\u201021 (miR\u201021) in K\u2010Ras\u2010driven p53\u2010deleted genetically engineered mouse models of PDAC. Strikingly, loss of miR\u201021 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\u2010restraining myofibroblasts and a massive infiltrate of immune cells were salient phenotypic features of global miR\u201021 loss. Stromal miR\u201021 activity was required for induction of tumor\u2010restraining myofibroblasts in in vivo isograft transplantation experiments. Low miR\u201021 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\u2010suppressive function of miR\u201021 in in vivo PDAC models. These results have important clinical implications for anti\u2010miR\u201021\u2010based inhibitory therapeutic approaches under consideration for PDAC and other cancer types. Mechanistic dissection of the cell\u2010intrinsic role of miR\u201021 in cancer\u2010associated fibroblasts and other cell types will be needed to inform best strategies for pharmacological modulation of miR\u201021 activity to remodel the tumor microenvironment and enhance treatment response in PDAC.<\/jats:p>","DOI":"10.1002\/ijc.33041","type":"journal-article","created":{"date-parts":[[2020,5,10]],"date-time":"2020-05-10T11:04:15Z","timestamp":1589108655000},"page":"2265-2278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Loss of <scp>microRNA<\/scp>\u201021 leads to profound stromal remodeling and short survival in <scp>K\u2010Ras<\/scp>\u2010driven mouse models of pancreatic cancer"],"prefix":"10.1002","volume":"147","author":[{"given":"Josh","family":"Schipper","sequence":"first","affiliation":[{"name":"Van Andel Research Institute  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Westerhuis","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Beddows","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zach","family":"Madaj","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Monsma","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galen","family":"Hostetter","sequence":"additional","affiliation":[{"name":"Van Andel Research Institute  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matti","family":"Kiupel","sequence":"additional","affiliation":[{"name":"Veterinary Diagnostic Laboratory Michigan State University  Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose R.","family":"Conejo\u2010Garcia","sequence":"additional","affiliation":[{"name":"Department of Immunology H. 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