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

by Gloria Gonzalez Curto, Audrey Der Vartanian, Youcef El-Mokhtar Frarma, Line Manceau, Lorenzo Baldi, Selene Prisco, Nabila Elarouci, Fr édéric Causeret, Daniil Korenkov, Muriel Rigolet, Frédéric Aurade, Aurélien De Reynies, Vincent Contremoulins, Frédéric Relaix, Orestis Faklaris, James Briscoe, Pascale Gilardi-Hebenstreit, Vanessa Ribes 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 express ion of tumour driver genes, they only inefficiently promote malignant transformationin vivo. The reason for this is unclear. To address this, we developed anin 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 tha...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research