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.
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
PAX3 Transcription Factor
/ genetics
PAX7 Transcription Factor
/ genetics
Paired Box Transcription Factors
/ genetics
Rhabdomyosarcoma, Alveolar
/ genetics
S Phase
/ genetics
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
28
05
2020
accepted:
02
10
2020
revised:
23
11
2020
pubmed:
12
11
2020
medline:
7
1
2021
entrez:
11
11
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33175861
doi: 10.1371/journal.pgen.1009164
pii: PGENETICS-D-20-00825
pmc: PMC7682867
doi:
Substances chimiques
CCND1 protein, human
0
MYCN protein, human
0
N-Myc Proto-Oncogene Protein
0
Oncogene Proteins, Fusion
0
PAX3 Transcription Factor
0
PAX3 protein, human
0
PAX3-FOXO1A fusion protein, human
0
PAX7 Transcription Factor
0
PAX7 protein, human
0
PAX7-FOXO1A fusion protein, human
0
Paired Box Transcription Factors
0
Cyclin D1
136601-57-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009164Subventions
Organisme : Cancer Research UK
ID : FC001051
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001051
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001051
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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