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Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers

Ewing sarcoma (EwS) is an aggressive pediatric bone cancer in need of more effective therapies than currently available. Most research into novel targeted therapeutic approaches is focused on the fusion oncogene EWSR1-FLI1, which is the genetic hallmark of this disease. In this study, a broad range...

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Autores principales: Tsafou, Kalliopi, Katschnig, Anna Maria, Radic-Sarikas, Branka, Mutz, Cornelia Noëlle, Iljin, Kristiina, Schwentner, Raphaela, Kauer, Maximilian O., Mühlbacher, Karin, Aryee, Dave N.T., Westergaard, David, Haapa-Paananen, Saija, Fey, Vidal, Superti-Furga, Giulio, Toretsky, Jeffrey, Brunak, Søren, Kovar, Heinrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089552/
https://www.ncbi.nlm.nih.gov/pubmed/30123424
http://dx.doi.org/10.18632/oncotarget.25760
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author Tsafou, Kalliopi
Katschnig, Anna Maria
Radic-Sarikas, Branka
Mutz, Cornelia Noëlle
Iljin, Kristiina
Schwentner, Raphaela
Kauer, Maximilian O.
Mühlbacher, Karin
Aryee, Dave N.T.
Westergaard, David
Haapa-Paananen, Saija
Fey, Vidal
Superti-Furga, Giulio
Toretsky, Jeffrey
Brunak, Søren
Kovar, Heinrich
author_facet Tsafou, Kalliopi
Katschnig, Anna Maria
Radic-Sarikas, Branka
Mutz, Cornelia Noëlle
Iljin, Kristiina
Schwentner, Raphaela
Kauer, Maximilian O.
Mühlbacher, Karin
Aryee, Dave N.T.
Westergaard, David
Haapa-Paananen, Saija
Fey, Vidal
Superti-Furga, Giulio
Toretsky, Jeffrey
Brunak, Søren
Kovar, Heinrich
author_sort Tsafou, Kalliopi
collection PubMed
description Ewing sarcoma (EwS) is an aggressive pediatric bone cancer in need of more effective therapies than currently available. Most research into novel targeted therapeutic approaches is focused on the fusion oncogene EWSR1-FLI1, which is the genetic hallmark of this disease. In this study, a broad range of 3,325 experimental compounds, among them FDA approved drugs and natural products, were screened for their effect on EwS cell viability depending on EWS-FLI1 expression. In a network-based approach we integrated the results from drug perturbation screens and RNA sequencing, comparing EWS-FLI1-high (normal expression) with EWS-FLI1-low (knockdown) conditions, revealing novel interactions between compounds and EWS-FLI1 associated biological processes. The top candidate list of druggable EWS-FLI1 targets included genes involved in translation, histone modification, microtubule structure, topoisomerase activity as well as apoptosis regulation. We confirmed our in silico results using viability and apoptosis assays, underlining the applicability of our integrative and systemic approach. We identified differential sensitivities of Ewing sarcoma cells to BCL-2 family inhibitors dependent on the EWS-FLI1 regulome including altered MCL-1 expression and subcellular localization. This study facilitates the selection of effective targeted approaches for future combinatorial therapies of patients suffering from Ewing sarcoma.
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spelling pubmed-60895522018-08-17 Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers Tsafou, Kalliopi Katschnig, Anna Maria Radic-Sarikas, Branka Mutz, Cornelia Noëlle Iljin, Kristiina Schwentner, Raphaela Kauer, Maximilian O. Mühlbacher, Karin Aryee, Dave N.T. Westergaard, David Haapa-Paananen, Saija Fey, Vidal Superti-Furga, Giulio Toretsky, Jeffrey Brunak, Søren Kovar, Heinrich Oncotarget Research Paper Ewing sarcoma (EwS) is an aggressive pediatric bone cancer in need of more effective therapies than currently available. Most research into novel targeted therapeutic approaches is focused on the fusion oncogene EWSR1-FLI1, which is the genetic hallmark of this disease. In this study, a broad range of 3,325 experimental compounds, among them FDA approved drugs and natural products, were screened for their effect on EwS cell viability depending on EWS-FLI1 expression. In a network-based approach we integrated the results from drug perturbation screens and RNA sequencing, comparing EWS-FLI1-high (normal expression) with EWS-FLI1-low (knockdown) conditions, revealing novel interactions between compounds and EWS-FLI1 associated biological processes. The top candidate list of druggable EWS-FLI1 targets included genes involved in translation, histone modification, microtubule structure, topoisomerase activity as well as apoptosis regulation. We confirmed our in silico results using viability and apoptosis assays, underlining the applicability of our integrative and systemic approach. We identified differential sensitivities of Ewing sarcoma cells to BCL-2 family inhibitors dependent on the EWS-FLI1 regulome including altered MCL-1 expression and subcellular localization. This study facilitates the selection of effective targeted approaches for future combinatorial therapies of patients suffering from Ewing sarcoma. Impact Journals LLC 2018-07-24 /pmc/articles/PMC6089552/ /pubmed/30123424 http://dx.doi.org/10.18632/oncotarget.25760 Text en Copyright: © 2018 Tsafou et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Tsafou, Kalliopi
Katschnig, Anna Maria
Radic-Sarikas, Branka
Mutz, Cornelia Noëlle
Iljin, Kristiina
Schwentner, Raphaela
Kauer, Maximilian O.
Mühlbacher, Karin
Aryee, Dave N.T.
Westergaard, David
Haapa-Paananen, Saija
Fey, Vidal
Superti-Furga, Giulio
Toretsky, Jeffrey
Brunak, Søren
Kovar, Heinrich
Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers
title Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers
title_full Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers
title_fullStr Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers
title_full_unstemmed Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers
title_short Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers
title_sort identifying the druggable interactome of ews-fli1 reveals mcl-1 dependent differential sensitivities of ewing sarcoma cells to apoptosis inducers
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089552/
https://www.ncbi.nlm.nih.gov/pubmed/30123424
http://dx.doi.org/10.18632/oncotarget.25760
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