MicroRNAs of themir-17~92cluster regulate multiple aspects of pancreatic tumor development and progression

// Brian Quattrochi 1 , Anushree Gulvady 2 , David R. Driscoll 1 , Makoto Sano 3 , David S. Klimstra 4 , Christopher E. Turner 2 , Brian C. Lewis 1, 5, 6 1 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA 2 Department of Cell and Developmental Biology, State University of New York Upstate Medical Center, Syracuse, NY 13210, USA 3 Division of Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Itabashi-ku, Tokyo, 173-8610, Japan 4 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 5 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA 6 Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA 01605, USA Correspondence to: Brian C. Lewis, email: Brian.Lewis@umassmed.edu Keywords: pancreatic cancer, mir-17~92, PanIN, regression, invasion Received: May 30, 2016 Accepted: March 08, 2017 Published: March 16, 2017 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by resistance to currently employed chemotherapeutic approaches. Members of the mir-17~92 cluster of microRNAs (miRNAs) are upregulated in PDAC, but the precise roles of these miRNAs in PDAC are unknown. Using genetically engineered mouse models, we show that loss of mir-17~92 reduces ERK pathway activation downstream of mutant KRAS and promotes the regression of KRAS G12D -driven precursor pancreatic intraepithelial neoplasias (PanINs) and their replacement by normal exocrine tissue. In a PDAC model driven by concomitant KRAS G12D expression and Trp53 heterozygosity, mir-17~92 deficiency extended the survival of mice that lacked distant metastasis. Moreover, mir-17~92 -deficient PDAC cell lines display reduced invasion activity in transwell assays, form fewer invadopodia rosettes than mir-17~92 -competent cell lines and are less able to degrade extracellular matrix. Specific inhibition of miR-19 family miRNAs with antagomirs recapitulates these phenotypes, suggesting that miR-19 family miRNAs are important mediators of PDAC cell invasion. Together these data demonstrate an oncogenic role for mir-17~92 at multiple stages of pancreatic tumorigenesis and progression; specifically, they link this miRNA cluster to ERK pathway activation and precursor lesion maintenance in vivo and identify a novel role for miR-19 family miRNAs in promoting cancer cell invasion.