A genome‐scale screen reveals context‐dependent ovarian cancer sensitivity to miRNA overexpression. Issue 12 (11th December 2015)

• Record Type: Journal Article
• Authors: Shields, Benjamin B; Pecot, Chad V; Gao, Hua; McMillan, Elizabeth; Potts, Malia; Nagel, Christa; Purinton, Scott; Wang, Ying; Ivan, Cristina; Kim, Hyun Seok; Borkowski, Robert J; Khan, Shaheen; Rodriguez‐Aguayo, Cristian; Lopez‐Berestein, Gabriel; Lea, Jayanthi; Gazdar, Adi; Baggerly, Keith A; Sood, Anil K; White, Michael A
• Is Part Of: Molecular systems biology. Volume 11:Issue 12(2015:Dec.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-12-11
• Subjects: cancer -- cancer genetics -- microRNA -- miRNA -- ovarian cancer; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20156308
• Languages: English
• ISSNs: 1744-4292

Abstract

Abstract: Large‐scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome‐scale, gain‐of‐function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor‐suppressive characteristics in vivo . A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA‐mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease. Synopsis: A genomewide miRNA mimic toxicity screen indicates common and selective vulnerabilities of epithelial ovarian cancer cells. Follow‐up analyses offer mechanistic insights into the selective sensitivity of ovarian cancer cells to select miRNAs. Screening the sensitivity of 16 ovarian cancer cell lines to 400 miRNA mimics reveals miRNAs with broad and selective effects. miR‐181 and miR‐155 are selectively toxic in chemoresistant ovarian cancer cells through dual modulation of TGFβ and AKT signaling. miR‐517a targets a common vulnerability, primarily via its target ARCN1. miR‐124 is selectively toxic, mainly by inducing terminal cell differentiation via its target SIX4. Abstract : A genomewide miRNA mimic toxicity screen indicates common and selective vulnerabilities of epithelial ovarian cancer cells. Follow‐up analyses offer mechanistic insights into the selective sensitivity of ovarian cancer cells to select miRNAs.