Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.

MicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of...

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Autores principales:	Davis T Weaver, Kathleen I Pishas, Drew Williamson, Jessica Scarborough, Stephen L Lessnick, Andrew Dhawan, Jacob G Scott
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d3d3a5fa7c66497d85ed284850f43e42
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spelling	oai:doaj.org-article:d3d3a5fa7c66497d85ed284850f43e422021-12-02T19:57:59ZNetwork potential identifies therapeutic miRNA cocktails in Ewing sarcoma.1553-734X1553-735810.1371/journal.pcbi.1008755https://doaj.org/article/d3d3a5fa7c66497d85ed284850f43e422021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1008755https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358MicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of the broad effects miRNAs may have on different cells and tissues, trials of miRNA therapies have struggled due to severe toxicity and unanticipated immune response. In order to overcome this hurdle, 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 while avoiding repression of essential housekeeping genes. We first characterized 6 Ewing sarcoma cell lines using mRNA 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. We then identified miRNAs and combinations of miRNAs that preferentially act to repress mRNA targets with the greatest influence on network potential. Our analysis identified TRIM25, APP, ELAV1, RNF4, and HNRNPL as ideal mRNA targets for Ewing sarcoma therapy. Using predicted miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as candidate optimal miRNAs for preferential repression of these targets. Ultimately, our work, as exemplified in the case of Ewing sarcoma, describes a novel pipeline by which personalized miRNA cocktails can be designed to maximally perturb gene networks contributing to cancer progression.Davis T WeaverKathleen I PishasDrew WilliamsonJessica ScarboroughStephen L LessnickAndrew DhawanJacob G ScottPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 10, p e1008755 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Davis T Weaver Kathleen I Pishas Drew Williamson Jessica Scarborough Stephen L Lessnick Andrew Dhawan Jacob G Scott Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.
description	MicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of the broad effects miRNAs may have on different cells and tissues, trials of miRNA therapies have struggled due to severe toxicity and unanticipated immune response. In order to overcome this hurdle, 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 while avoiding repression of essential housekeeping genes. We first characterized 6 Ewing sarcoma cell lines using mRNA 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. We then identified miRNAs and combinations of miRNAs that preferentially act to repress mRNA targets with the greatest influence on network potential. Our analysis identified TRIM25, APP, ELAV1, RNF4, and HNRNPL as ideal mRNA targets for Ewing sarcoma therapy. Using predicted miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as candidate optimal miRNAs for preferential repression of these targets. Ultimately, our work, as exemplified in the case of Ewing sarcoma, describes a novel pipeline by which personalized miRNA cocktails can be designed to maximally perturb gene networks contributing to cancer progression.
format	article
author	Davis T Weaver Kathleen I Pishas Drew Williamson Jessica Scarborough Stephen L Lessnick Andrew Dhawan Jacob G Scott
author_facet	Davis T Weaver Kathleen I Pishas Drew Williamson Jessica Scarborough Stephen L Lessnick Andrew Dhawan Jacob G Scott
author_sort	Davis T Weaver
title	Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.
title_short	Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.
title_full	Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.
title_fullStr	Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.
title_full_unstemmed	Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.
title_sort	network potential identifies therapeutic mirna cocktails in ewing sarcoma.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/d3d3a5fa7c66497d85ed284850f43e42
work_keys_str_mv	AT davistweaver networkpotentialidentifiestherapeuticmirnacocktailsinewingsarcoma AT kathleenipishas networkpotentialidentifiestherapeuticmirnacocktailsinewingsarcoma AT drewwilliamson networkpotentialidentifiestherapeuticmirnacocktailsinewingsarcoma AT jessicascarborough networkpotentialidentifiestherapeuticmirnacocktailsinewingsarcoma AT stephenllessnick networkpotentialidentifiestherapeuticmirnacocktailsinewingsarcoma AT andrewdhawan networkpotentialidentifiestherapeuticmirnacocktailsinewingsarcoma AT jacobgscott networkpotentialidentifiestherapeuticmirnacocktailsinewingsarcoma
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Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.

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