title: Tumor-specific chromosome mis-segregation controls cancer plasticity by maintaining tumor heterogeneity.
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 mis-segregation, 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.
authors.affiliation: Department of Biological Chemistry, University of California Irvine, Irvine, California, United States of America.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Hu
authors.forename: Ning
authors.initials: N
authors.lastname: Ru
authors.forename: Huasheng
authors.initials: H
authors.lastname: Xiao
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chaturbedi
authors.forename: Neil T
authors.initials: NT
authors.lastname: Hoa
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Tian
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Ke
authors.forename: Fengrong
authors.initials: F
authors.lastname: Yan
authors.forename: Jodi
authors.initials: J
authors.lastname: Nelson
authors.forename: Zhenzhi
authors.initials: Z
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Gramer
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Eric
authors.initials: E
authors.lastname: Siegel
authors.forename: Xiaona
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Jia
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jadus
authors.forename: Charles L
authors.initials: CL
authors.lastname: Limoli
authors.forename: Mark E
authors.initials: ME
authors.lastname: Linskey
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xing
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002877:Chromosomes, Human; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction