TY - JOUR
T1 - Tumor-specific chromosome mis-segregation controls cancer plasticity by maintaining tumor heterogeneity
AU - Hu, Yuanjie
AU - Ru, Ning
AU - Xiao, Huasheng
AU - Chaturbedi, Abhishek
AU - Hoa, Neil T.
AU - Tian, Xiao Jun
AU - Zhang, Hang
AU - Ke, Chao
AU - Yan, Fengrong
AU - Nelson, Jodi
AU - Li, Zhenzhi
AU - Gramer, Robert
AU - Yu, Liping
AU - Siegel, Eric
AU - Zhang, Xiaona
AU - Jia, Zhenyu
AU - Jadus, Martin R.
AU - Limoli, Charles L.
AU - Linskey, Mark E.
AU - Xing, Jianhua
AU - Zhou, Yi Hong
PY - 2013/11/25
Y1 - 2013/11/25
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0080898
DO - 10.1371/journal.pone.0080898
M3 - Article
C2 - 24282558
AN - SCOPUS:84896731586
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 11
M1 - e80898
ER -