The mechanism of replication stress-induced nuclear enlargement and its impact on cancer cell metastasis

Abstract

Abnormalities in nuclear size and shape are prominent characteristics of cancer cells. Despite advances in sequencing technology, microscopic examination of cell nuclear morphology remains crucial in cancer diagnosis. While studies have explored the correlation between nuclear size and cancer progression and prognosis, the mechanism underlying abnormal nuclear size and its impact on cancer development have not been fully elucidated. In this study, I analyzed genome-wide siRNA library screening data to gain insights into the disturbance of nuclear size homeostasis. I discovered that genes related to the DNA replication stress response are closely associated with an increase in nuclear size. Specifically, I identified a mechanism wherein DNA replication stress induced by the inhibition of RAD51 gene expression leads to an increase in nuclear size mediated by the kinase ATR. ATR activity appears to increase nuclear size by promoting actin polymerization inside the nucleus. This DNA replication stress was found to be higher in the center of the tumor in vivo, coinciding with increased nuclear size in the tumor center. These results elucidate the morphological heterogeneity of cell nuclei based on their location within the tumor. Furthermore, the increase in nuclear size due to replication stress demonstrated an inhibitory effect on cell invasion. This suggests that cancer cells at the periphery, rather than those at the center of the tumor with enlarged nuclei, may play a primary role in metastasis. In conclusion, this study proposes that the increased nuclear size in cancer progression may result from DNA replication stress associated with intratumoral location rather than genetic differences, and that this increased nuclear size has implications for cancer metastasis. These findings advance our understanding of the causes and consequences of disruption of nuclear size homeostasis in cancer cells.