A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression
Authors
Benjamin B Shields ; Chad V Pecot ; Hua Gao ; Elizabeth McMillan ; Malia Potts ; Christa Nagel ; Scott Purinton ; Ying Wang ; Cristina Ivan ; Hyun Seok Kim ; Robert J Borkowski ; Shaheen Khan ; Cristian Rodriguez-Aguayo ; Gabriel Lopez-Berestein ; Jayanthi Lea ; Adi Gazdar ; Keith A Baggerly ; Anil K Sood ; Michael A White
cancer ; cancer genetics ; miRNA ; microRNA ; ovarian cancer
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.