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Oncogene. 2019 Aug;38(33):6083-6094. doi: 10.1038/s41388-019-0859-6. Epub 2019 Jul 3.

Fusion-mediated chromosomal instability promotes aneuploidy patterns that resemble human tumors.

Author information

1
INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31037, Toulouse, France.
2
INSERM U1218, 229 cours de l'Argonne, 33076, Bordeaux, France.
3
University of Bordeaux, 146 rue Léo Saignat, 33000, Bordeaux, France.
4
University of Toulouse 3, Paul Sabatier, 118 route de Narbonne, 31062, Toulouse, Cedex 9, France.
5
Institut Claudius Régaud, IUCT-Oncopole, Toulouse, France.
6
Department of Biopathology, Bergonié Institute, 229 cours de l'Argonne, 33076, Bordeaux, France.
7
Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, Toulouse, France.
8
INSERM U1053, 146 rue Léo Saignat, 33000, Bordeaux, France.
9
Animal Facility A2, Bordeaux University, 146 rue Léo Saignat, 33000, Bordeaux, France.
10
INSERM U1212 - CNRS UMR 5320, ARNA Laboratory, 33000, Bordeaux, France.
11
INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31037, Toulouse, France. frederic.chibon@inserm.fr.
12
Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, Toulouse, France. frederic.chibon@inserm.fr.

Abstract

Oncogenesis is considered to result from chromosomal instability, in addition to oncogene and tumor-suppressor alterations. Intermediate to aneuploidy and chromosomal instability, genome doubling is a frequent event in tumor development but the mechanisms driving tetraploidization and its impact remain unexplored. Cell fusion, one of the pathways to tetraploidy, is a physiological process involved in mesenchymal cell differentiation. Besides simple genome doubling, cell fusion results in the merging of two different genomes that can be destabilized upon proliferation. By testing whether cell fusion is involved in mesenchymal oncogenesis, we provide evidence that it induces genomic instability and mediates tumor initiation. After a latency period, the tumor emerges with the cells most suited for its development. Furthermore, hybrid tumor genomes were stabilized after this selection process and were very close to those of human pleomorphic mesenchymal tumors. Thus genome restructuring triggered by cell fusion may account for the chromosomal instability involved in oncogenesis.

PMID:
31270395
DOI:
10.1038/s41388-019-0859-6

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