PT  - JOURNAL ARTICLE
AU  - Davis T. Weaver
AU  - Kathleen I. Pishas
AU  - Drew Williamson
AU  - Jessica Scarborough
AU  - Stephen L. Lessnick
AU  - Andrew Dhawan
AU  - Jacob G. Scott
TI  - Network potential identifies therapeutic <em>miRNA</em> cocktails in Ewing sarcoma
AID  - 10.1101/854695
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 854695
4099  - http://biorxiv.org/content/early/2020/03/05/854695.short
4100  - http://biorxiv.org/content/early/2020/03/05/854695.full
AB  - Introduction Micro-RNA (miRNA)-based therapies are an emerging class of cancer therapies with many potential applications in the field. Because of the broad effects miRNAs can have on different cells and tissues, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets.Methods We first characterized 6 Ewing sarcoma cell lines using paired mRNA and miRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential. After identifying these mRNA targets, we identified miRNAs and combinations of miRNAs that preferentially act to repress these targets.Results We identified TRIM25, APP, ELAV1, RNF4, XPO1 as ideal protein targets for Ewing sarcoma therapy. Using miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as the optimal miRNAs for preferential repression of these targets.Discussion In this work, we applied a novel pipeline for identification of miRNA candidates for cancer therapy, using Ewing sarcoma as a model system.