Supplementary Figure 1 shows Nestin expression. Supplementary Figure 2 shows Sox2 expression. Supplementary Figure 3 shows differentiation of GNS cells. Supplementary Figure 4 shows checkpoint assay and FISH data. Supplementary Figure 5 shows karyotypes of GliNS2 cells. Supplementary Figure 6 shows p53 and p21 response. Supplementary Figure 7 shows FISH and karyotypes of PDX lines.Supplementary Figure 8 shows Sox2 and Nestin expression in stable GFP expressing lines. Supplementary Figure 9 shows limiting dilution assay in vitro. Supplementary Figure 10 shows FACS profiles for growth assay. Supplementary Figure 11 shows astrocyte differentiation of GFP expressing lines.
ARTICLE 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.Significance: 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
