title: Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells.
abstract: Tumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection and evolution in tumors. Tumor-initiating cells (TIC) that are responsible for tumorigenesis are a source of functional cellular heterogeneity, whereas chromosomal instability (CIN) is a source of karyotypic genetic diversity. However, the extent that CIN contributes to TIC genetic diversity and its relationship to TIC function remains unclear. Here, we demonstrate that glioblastoma TICs display CIN with lagging chromosomes at anaphase and extensive nonclonal chromosome copy-number variations. Elevating the basal chromosome missegregation rate in TICs decreases both proliferation and the stem-like phenotype of TICs in vitro Consequently, tumor formation is abolished in an orthotopic mouse model. These results demonstrate that TICs generate genetic heterogeneity within tumors, but that TIC function is impaired if the rate of genetic change is elevated above a tolerable threshold.
  
  
  
  Genetic heterogeneity among TICs may produce advantageous karyotypes that lead to therapy resistance and relapse; however, we found that TICs have an upper tolerable limit for CIN. Thus, increasing the chromosome missegregation rate offers a new therapeutic strategy to eliminate TICs from tumors. Cancer Discov; 6(5); 532-45. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Godek
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Monica
authors.initials: M
authors.lastname: Venere
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Quilian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Mills
authors.affiliation: Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: William F
authors.initials: WF
authors.lastname: Hickey
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris Cotton Cancer Center, Lebanon, New Hampshire. duane.a.compton@dartmouth.edu.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Compton
mesh_terms: D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D020090:Chromosome Segregation; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*
chemical_list: D015415:Biomarkers