Environmental stresses induce karyotypic instability in colorectal cancer cells Zhihao Tan, Yong Jie Andrew Chan, Ying Jie Karen Chua, Samuel D. Rutledge, Norman Pavelka, Daniela Cimini, and Giulia Rancati Molecular Biology of the Cell 2019 30:1, 42-55
Understanding how cells acquire genetic mutations is a fundamental biological question with implications for many different areas of biomedical research, ranging from tumor evolution to drug resistance. While karyotypic heterogeneity is a hallmark of cancer cells, few mutations causing chromosome instability have been identified in cancer genomes, suggesting a nongenetic origin of this phenomenon. We found that in vitro exposure of karyotypically stable human colorectal cancer cell lines to environmental stress conditions triggered a wide variety of chromosomal changes and karyotypic heterogeneity. At the molecular level, hyperthermia induced polyploidization by perturbing centrosome function, preventing chromosome segregation, and attenuating the spindle assembly checkpoint. The combination of these effects resulted in mitotic exit without chromosome segregation. Finally, heat-induced tetraploid cells were on the average more resistant to chemotherapeutic agents. Our studies suggest that environmental perturbations promote karyotypic heterogeneity and could contribute to the emergence of drug resistance.
This study was funded by an A*STAR Investigatorship (Ref. No. 1437a00119) awarded to G.R. Work in the Cimini lab was partly supported by National Science Foundation grant MCB-1517506.