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

PLoS Genet. 2020 Nov 11;16(11):e1009164. doi: 10.1371/journal.pgen.1009164. eCollection 2020 Nov.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy
  • Cell Transdifferentiation / genetics*
  • Cell Transformation, Neoplastic / genetics*
  • Chick Embryo
  • Child
  • Cyclin D1 / genetics
  • Datasets as Topic
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • N-Myc Proto-Oncogene Protein / genetics
  • Neoplasm Invasiveness / genetics
  • Neural Stem Cells / pathology
  • Neural Tube / cytology
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • PAX3 Transcription Factor / genetics
  • PAX3 Transcription Factor / metabolism
  • PAX7 Transcription Factor / genetics
  • PAX7 Transcription Factor / metabolism
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism*
  • Rhabdomyosarcoma, Alveolar / genetics*
  • Rhabdomyosarcoma, Alveolar / pathology
  • S Phase / genetics


  • CCND1 protein, human
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Oncogene Proteins, Fusion
  • PAX3 Transcription Factor
  • PAX3 protein, human
  • PAX3-FOXO1A fusion protein, human
  • PAX7 Transcription Factor
  • PAX7 protein, human
  • PAX7-FOXO1A fusion protein, human
  • Paired Box Transcription Factors
  • Cyclin D1