Hypoxia-driven changes in nuclear morphology as a determinant of cell migration.

Metastatic pancreatic cancer is marked by extreme hypoxia and resistance to current therapies, necessitating urgent need for novel treatment strategies. Here, we investigate how hypoxia-mimetic conditions induced by cobalt chloride drive pancreatic cancer cell invasion by modulating cellular and nuclear mechanics. Through microscopic imaging, atomic force microscopy, and mass spectrometry, we show that hypoxia induces changes in cellular morphology by reducing cell spread area, enhancing filopodia formation, and decreasing actin anisotropy, promoting a migratory and invasive phenotype. We next demonstrated that hypoxia alters nuclear morphological and mechanical attributes, reducing nuclear size and stiffness, accompanied by decreased lamin A expression, thereby facilitating nuclear deformability required for cell migration. Notably, we observed substantial wrinkling of the nuclear envelope in pancreatic cancer under hypoxia, highlighting it as a potentially efficient mechanical phenotype for pancreatic cancer. Finally, hypoxia triggers specific changes in the nuclear lipidome and proteome, including increased lipid saturation and acyl chain length with lower expression of linker of nucleo-skeleton and cytoskeleton proteins, aligning with altered nuclear mechanics. Together, our findings reveal a mechanoadaptive response of hypoxia that links biophysical remodeling with metastatic potential, offering new possibilities for using mechanics-targeted treatments to limit cancer cell migration, hence reducing metastasis.