Tetraploidization of Immortalized Myoblasts Induced by Cell Fusion Drives Myogenic Sarcoma Development with DMD Deletion

Whole-genome doubling is the second most frequent genomic event, after TP53 alterations, in advanced solid tumors and is associated with poor prognosis. Tetraploidization step will lead to aneuploidy and chromosomic rearrangements. The mechanism leading to tetraploid cells is important since endorep...

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Vydáno v:Cancers Ročník 12; číslo 5; s. 1281
Hlavní autoři: Merle, Candice, Thébault, Noémie, LeGuellec, Sophie, Baud, Jessica, Pérot, Gaëlle, Lesluyes, Tom, Delespaul, Lucile, Lartigue, Lydia, Chibon, Frédéric
Médium: Journal Article
Jazyk:angličtina
Vydáno: Switzerland MDPI AG 19.05.2020
MDPI
Témata:
Aneuploidy
Cancer
Cell activation
Cell fusion
Chromosomes
Cloning
Cytokinesis
Deoxyribonucleic acid
DNA
Genomes
Hybrids
Hypotheses
Invasiveness
Life Sciences
Metastases
Mitosis
Myoblasts
p53 Protein
Physiology
Population
Sarcoma
Solid tumors
Tumorigenesis
Tumors
sarcoma
dystrophin
genomic instability
cell fusion
ISSN:2072-6694, 2072-6694
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Shrnutí:Whole-genome doubling is the second most frequent genomic event, after TP53 alterations, in advanced solid tumors and is associated with poor prognosis. Tetraploidization step will lead to aneuploidy and chromosomic rearrangements. The mechanism leading to tetraploid cells is important since endoreplication, abortive cytokinesis and cell fusion could have distinct consequences. Unlike processes based on duplication, cell fusion involves the merging of two different genomes, epigenomes and cellular states. Since it is involved in muscle differentiation, we hypothesized that it could play a role in the oncogenesis of myogenic cancers. Spontaneous hybrids, but not their non-fused immortalized myoblast counterparts they are generated from, induced tumors in mice. Unstable upon fusion, the hybrid genome evolved from initial mitosis to tumors with a highly rearranged genome. This genome remodeling finally produced targeted DMD deletions associated with replicative stress, isoform relocalization and metastatic spreading, exactly as observed in human myogenic sarcomas. In conclusion, these results draw a model of myogenic oncogenesis in which cell fusion and oncogene activation combine to produce pleomorphic aggressive sarcomas.
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ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12051281