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Tumor-Specific Chromosome Mis-Segregation Controls Cancer Plasticity by Maintaining Tumor Heterogeneity

Figure 6

Mathematical modeling of experimental data with changes in population equilibrium from homogeneity to heterogeneity.

A, schematic illustration of the working mechanism with Chr7-MS resulting in heterogeneous subpopulations and cellular phenotype inter-conversion, with STIC inhibiting growth of TMC and/or TMC stimulating growth of STIC. The Chr7 composition was shown for representative subpopulation cells in U251, based on metaphase FISH.A higher growth rate for TMC (r3) was shown compared to that for STIC (r2). Cells marked by black circles were seen in metaphase FISH analysis, suggesting their ability to grow in vitro. Cells marked by gray boxes were not seen in metaphase FISH analysis, suggesting they are unable, or have very low ability to grow in vitro. B, changes in population equilibrium from homogeneity to heterogeneity in NS1 after serial, three-day passages in SA-culture conditions, using the same cell plating density (5×105/100 mm dish), with cell types determined by FISH (experimental) and then modeled using different parameters as detailed in Methods. C. changes in cell growth speed as measured or predicted by various mathematical models. D, s.c. tumorigenicity assay showing the TMC features of 3Chr7:2n,1d cells converted from STIC by increasing percentage tumor onset (a tumor size of ∼50 mm3). The plot with percent uses percents computed via the Kaplan-Meier method. Log-rank test for trend with 3Chr7:2n,1d cells shows two-sided P<0.0001.

Figure 6