Mechanical stress during confined migration drives chromosomes mis-segregation and c-MYC amplifications

Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer, driving intra-tumoral heterogeneity and phenotypic adaptation in complex micro-environments. Recent evidence links mechanical stress to CIN. Notably, distant metastases often acquire novel mutations not seen in the primary tumor, suggesting a genotoxic effect of interstitial migration. Here we combine live cell imaging, micro-fluidic approaches and scRNA-seq to investigate the impact of mechanical stress during mitosis on genetic heterogeneity in cancer cells undergoing confined migration. We found that tumor cells dividing across constrictions exhibit altered spindle pole organization, chromosome mis-segregations and micronuclei. Mechanical stress leads to gene copy number variations due to defective mitosis, and migration across constrictions up-regulates c-MYC oncogenic transcriptional signature via c-MYC locus amplifications. In conclusion, our study identifies mechanical stress during metastatic migration as a source of mitotic stress, CIN, aneuploidy and c-MYC amplifications. Understanding these mechanisms could represent an opportunity for novel therapeutic strategies to target metastasis and tumor cells genetic heterogeneity.