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The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition
The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expressio...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682867/ https://www.ncbi.nlm.nih.gov/pubmed/33175861 http://dx.doi.org/10.1371/journal.pgen.1009164 |
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author | Gonzalez Curto, Gloria Der Vartanian, Audrey Frarma, Youcef El-Mokhtar Manceau, Line Baldi, Lorenzo Prisco, Selene Elarouci, Nabila Causeret, Frédéric Korenkov, Daniil Rigolet, Muriel Aurade, Frédéric De Reynies, Aurélien Contremoulins, Vincent Relaix, Frédéric Faklaris, Orestis Briscoe, James Gilardi-Hebenstreit, Pascale Ribes, Vanessa |
author_facet | Gonzalez Curto, Gloria Der Vartanian, Audrey Frarma, Youcef El-Mokhtar Manceau, Line Baldi, Lorenzo Prisco, Selene Elarouci, Nabila Causeret, Frédéric Korenkov, Daniil Rigolet, Muriel Aurade, Frédéric De Reynies, Aurélien Contremoulins, Vincent Relaix, Frédéric Faklaris, Orestis Briscoe, James Gilardi-Hebenstreit, Pascale Ribes, Vanessa |
author_sort | Gonzalez Curto, Gloria |
collection | PubMed |
description | The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently promote malignant transformation in vivo. The reason for this is unclear. To address this, we developed an in ovo model to follow the response of spinal cord progenitors to PAX-FOXO1s. Our data demonstrate that PAX-FOXO1s, but not wild-type PAX3 or PAX7, trigger the trans-differentiation of neural cells into FP-RMS-like cells with myogenic characteristics. In parallel, PAX-FOXO1s remodel the neural pseudo-stratified epithelium into a cohesive mesenchyme capable of tissue invasion. Surprisingly, expression of PAX-FOXO1s, similar to wild-type PAX3/7, reduce the levels of CDK-CYCLIN activity and increase the fraction of cells in G1. Introduction of CYCLIN D1 or MYCN overcomes this PAX-FOXO1-mediated cell cycle inhibition and promotes tumour growth. Together, our findings reveal a mechanism that can explain the apparent limited oncogenicity of PAX-FOXO1 fusion transcription factors. They are also consistent with certain clinical reports indicative of a neural origin of FP-RMS. |
format | Online Article Text |
id | pubmed-7682867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-76828672020-12-02 The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition Gonzalez Curto, Gloria Der Vartanian, Audrey Frarma, Youcef El-Mokhtar Manceau, Line Baldi, Lorenzo Prisco, Selene Elarouci, Nabila Causeret, Frédéric Korenkov, Daniil Rigolet, Muriel Aurade, Frédéric De Reynies, Aurélien Contremoulins, Vincent Relaix, Frédéric Faklaris, Orestis Briscoe, James Gilardi-Hebenstreit, Pascale Ribes, Vanessa PLoS Genet Research Article The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently promote malignant transformation in vivo. The reason for this is unclear. To address this, we developed an in ovo model to follow the response of spinal cord progenitors to PAX-FOXO1s. Our data demonstrate that PAX-FOXO1s, but not wild-type PAX3 or PAX7, trigger the trans-differentiation of neural cells into FP-RMS-like cells with myogenic characteristics. In parallel, PAX-FOXO1s remodel the neural pseudo-stratified epithelium into a cohesive mesenchyme capable of tissue invasion. Surprisingly, expression of PAX-FOXO1s, similar to wild-type PAX3/7, reduce the levels of CDK-CYCLIN activity and increase the fraction of cells in G1. Introduction of CYCLIN D1 or MYCN overcomes this PAX-FOXO1-mediated cell cycle inhibition and promotes tumour growth. Together, our findings reveal a mechanism that can explain the apparent limited oncogenicity of PAX-FOXO1 fusion transcription factors. They are also consistent with certain clinical reports indicative of a neural origin of FP-RMS. Public Library of Science 2020-11-11 /pmc/articles/PMC7682867/ /pubmed/33175861 http://dx.doi.org/10.1371/journal.pgen.1009164 Text en © 2020 Gonzalez Curto et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Gonzalez Curto, Gloria Der Vartanian, Audrey Frarma, Youcef El-Mokhtar Manceau, Line Baldi, Lorenzo Prisco, Selene Elarouci, Nabila Causeret, Frédéric Korenkov, Daniil Rigolet, Muriel Aurade, Frédéric De Reynies, Aurélien Contremoulins, Vincent Relaix, Frédéric Faklaris, Orestis Briscoe, James Gilardi-Hebenstreit, Pascale Ribes, Vanessa The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition |
title | The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition |
title_full | The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition |
title_fullStr | The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition |
title_full_unstemmed | The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition |
title_short | The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition |
title_sort | pax-foxo1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by s phase entry inhibition |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682867/ https://www.ncbi.nlm.nih.gov/pubmed/33175861 http://dx.doi.org/10.1371/journal.pgen.1009164 |
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