A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression

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.

Source: Molecular Systems Biology - December 11, 2015 Category: Molecular Biology Authors: Shields, B. B., Pecot, C. V., Gao, H., McMillan, E., Potts, M., Nagel, C., Purinton, S., Wang, Y., Ivan, C., Kim, H. S., Borkowski, R. J., Khan, S., Rodriguez-Aguayo, C., Lopez-Berestein, G., Lea, J., Gazdar, A., Baggerly, K. A., Sood, A. K., White, M. A. Tags: Cancer, Chromatin, Epigenetics, Genomics & Functional Genomics Articles Source Type: research