期刊
FASEB JOURNAL
卷 32, 期 7, 页码 3502-3517出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201700247RR
关键词
genomic instability; aneuploidy; lagging chromosomes; invasive front; colorectal cancer
资金
- NIH
- CIBEREHD Program
- Instituto de Salud Carlos III
- European Regional Development Fund (ERDF) [CP13/00160, PI14/00783]
- European Commission MC-CIG (COLONGEVA)
- Spanish Association Against Cancer (AECC) [GCB13131592CAST]
- Agencia de Gestio d'Ajuts Universitaris i de Recerca, Generalitat de Catalunya [2014 SGR 135, 2014 SGR 903]
- National Service Foundation (NSF) [MCB-1517506]
- Ministerio de Educacion, Cultura y Deporte
- Ministerio de Ciencia e Innovacion
- Scientific and Technological Research Council of Turkey (TUBITAK) 2219 Program
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1517506] Funding Source: National Science Foundation
A considerable proportion of tumors exhibit aneuploid karyotypes, likely resulting from the progressive loss of chromosomes after whole-genome duplication. Here, by using isogenic diploid and near-tetraploid (4N) single-cell-derived clones from the same parental cell lines, we aimed at exploring how polyploidization affects cellular functions and how tetraploidy generates chromosome instability. Gene expression profiling in 4N clones revealed a significant enrichment of transcripts involved in cell cycle and DNA replication. Increased levels of replication stress in 4N cells resulted in DNA damage, impaired proliferation caused by a cell cycle delay during S phase, and higher sensitivity to S phase checkpoint inhibitors. In fact, increased levels of replication stress were also observed in nontransformed, proliferative posttetraploid RPE1 cells. Additionally, replication stress promoted higher levels of intercellular genomic heterogeneity and ongoing genomic instability, which could be explained by high rates of mitotic defects, and was alleviated by the supplementation of exogenous nucleosides. Finally, our data found that 4N cancer cells displayed increased migratory and invasive capacity, both in vitro and in primary colorectal tumors, indicating that tetraploidy can promote aggressive cancer cell behavior.-Wangsa, D., Quintanilla, I., Torabi, K., Vila-Casadesus, M., Ercilla, A., Klus, G., Yuce, Z., Galofre, C., Cuatrecasas, M., Lozano, J. J., Agell, N., Cimini, D., Castells, A., Ried, T., Camps, J. Near-tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness.
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