Targeting The Process Of Mitotic Chromosome Segregation As A Novel Sensitizing Target To Radiation Treatment

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy; however, the mechanism for this cell cycle-dependent vulnerability is unknown. Here, we used a combination of high-resolution microscopy, in vivo mouse model and a computational model to understand the relationship between mitotic errors in chromosome segregation and tumor cell viability after exposure to radiation therapy. We showed that treatment with IR led to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumor-derived cell lines. These mitotic errors generated an abundance of micronuclei that predisposed chromosomes to subsequent catastrophic pulverization, thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduced downstream chromosomal defects and significantly increased the viability of irradiated mitotic cells; furthermore, orthotopically transplanted human glioblastoma tumors, in which chromosome missegregation rates were reduced, were rendered markedly more resistant to IR exhibiting diminished markers of cell death in response to treatment. We then created a computational framework to understand the relationship between cellular viability and chromosome missegregation frequency. Using an experimentally inspired stochastic model, based on the potency and chromosomal distribution of oncogenes and tumor suppressor genes, we found that cancer cells have evolved to exist within a narrow range of chromosome missegregation rates that optimize phenotypic heterogeneity and clonal survival. Departure from this range dramatically reduced clonal fitness and limited subclonal diversity. Mapping of the aneuploid fitness landscape revealed a highly favorable, commonly observed, near-triploid state onto which evolving diploid and tetraploid-derived populations spontaneously converged, albeit at a much lower fitness cost for the latter. This work identifies a novel mitotic pathway for radiation-induced genome damage, which occurs outside of the primary nucleus and augments chromosomal breaks. It also offers a new quantitative and experimental insight onto the potential for targeting chromosome segregation during mitosis as a novel target to sensitize tumors to ionizing radiation. This relationship between radiation treatment and whole-chromosome missegregation can be exploited to modulate therapeutic response in a clinically relevant manner.