Mitosis down-regulates nuclear volume and resets nuclear envelope folding of cancer cells under prolonged confinement

During their life, mammalian cells are subjected to numerous mechanical constraints, especially in pathological contexts such as cancer. Recent studies have highlighted the central role of the nucleus in sensing mechanical cues, but they only focus on short periods of time, and so far, whether cells can adapt to prolonged confinement remains unknown. Here, we reveal the unsuspected role of mitosis in the long-term adaptation of nuclei to prolonged uniaxial confinement. For the colorectal cancer cell line investigated, following the first confined cell division, a new homeostatic state was reached by nuclei: they were smaller, and had reset the tension of their envelope. This adaptation through mitosis relied both on the nuclear tension sensor cPLA2 and the contractility machinery. We report for the first time a mechano-adaptation during mitosis, a process that could be crucial to adapt to stresses in the tumor microenvironment. We therefore anticipate that our work could provide new insight into cancer cell plasticity and cancer relapse. Significance StatementMost cell types undergo significant deformation throughout their life cycles. Immune cells must deform to navigate through dense matrices, while cancer cells in solid tumors experience squeezing from neighboring cells. The nucleus, central for many cell function, is the stiffest and largest organelle. Understanding its long-term response to spatial constraints is hence crucial yet largely unexplored. In this study, we investigate how a colorectal cancer cell line adapts to prolonged confined environments, with a particular focus on nuclear dynamics under continuous squeezing. Our groundbreaking findings reveal for the first time a mechano-adaptation during mitosis leading to a decrease in nuclear size. This research contributes to the fundamental understanding of cellular mechanosensing, opening new avenues for cancer biology research.