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Near‐tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness
Author(s) -
Wangsa Darawalee,
Quintanilla Isabel,
Torabi Keyvan,
VilaCasadesús Maria,
Ercilla Amaia,
Klus Gregory,
Yuce Zeynep,
Galofré Claudia,
Cuatrecasas Miriam,
José Lozano Juan,
Agell Neus,
Cimini Daniela,
Castells Antoni,
Ried Thomas,
Camps Jordi
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700247rr
Subject(s) - genome instability , chromosome instability , biology , cell cycle , mitosis , dna replication , gene duplication , replication timing , chromosome , genetics , cell growth , cancer cell , gene , cell , cancer research , dna damage , microbiology and biotechnology , cancer , dna
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‐Casadesús, M., Ercilla, A., Klus, G., Yuce, Z., Galofré, 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. FASEB J. 32, 3502–3517 (2018). www.fasebj.org