Tumor-specific chromosome mis-segregation controls cancer plasticity by maintaining tumor heterogeneity

Yuanjie Hu, Ning Ru, Huasheng Xiao, Abhishek Chaturbedi, Neil T. Hoa, Xiao Jun Tian, Hang Zhang, Chao Ke, Fengrong Yan, Jodi Nelson, Zhenzhi Li, Robert Gramer, Liping Yu, Eric Siegel, Xiaona Zhang, Zhenyu Jia, Martin R. Jadus, Charles L. Limoli, Mark E. Linskey, Jianhua XingYi Hong Zhou

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Aneuploidy with chromosome instability is a cancer hallmark. We studied chromosome 7 (Chr7) copy number variation (CNV) in gliomas and in primary cultures derived from them. We found tumor heterogeneity with cells having Chr7-CNV commonly occurs in gliomas, with a higher percentage of cells in high-grade gliomas carrying more than 2 copies of Chr7, as compared to low-grade gliomas. Interestingly, all Chr7-aneuploid cell types in the parental culture of established glioma cell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic glioma cultures dominated by different Chr7-aneuploid cell types. We found phenotypic divergence for cells following Chr7 missegregation, which benefited overall tumor growth in vitro and in vivo. Mathematical modeling suggested the involvement of chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor cell types. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneity could be enhanced by the existence of chromosomes with structural abnormality, in addition to their mis-segregations. Overall, our findings show, for the first time, the involvement of chromosome instability in maintaining tumor heterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers.

Original languageEnglish (US)
Article numbere80898
JournalPloS one
Volume8
Issue number11
DOIs
StatePublished - Nov 25 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hu, Y., Ru, N., Xiao, H., Chaturbedi, A., Hoa, N. T., Tian, X. J., Zhang, H., Ke, C., Yan, F., Nelson, J., Li, Z., Gramer, R., Yu, L., Siegel, E., Zhang, X., Jia, Z., Jadus, M. R., Limoli, C. L., Linskey, M. E., ... Zhou, Y. H. (2013). Tumor-specific chromosome mis-segregation controls cancer plasticity by maintaining tumor heterogeneity. PloS one, 8(11), [e80898]. https://doi.org/10.1371/journal.pone.0080898