Active regulation of contractility and ion transport drives "nuclear piston" mechanism of 3D migration in tumor cells

In the absence of protease activity, tumor cells can switch from the lamellipodia mode of migration to a lobopodial mode, characterized by the blunt, cylindrical protrusions. In this case, the nucleus acts as a piston and physically compartmentalizes the cytoplasm with a larger hydrostatic pressure in the anterior of the cell compared to the posterior. To quantitatively understand the biophysical mechanisms governing this pressure driven migration mode, we developed a model that considers the translocation of the nucleus driven by actomyosin contractility through Nesprin links. The movement of the nucleus leads to the exchange of ions and water with the microenvironment, driven by differences in electrostatic potential and osmotic and hydrostatic pressures. Our model predicts that actomyosin contractility, integrin-based cell adhesions, Nesprin links and the presence of intracellular negative charges associated with proteins and organic phosphates are essential for lobopodial migration. We also predict that influx of Calcium ions through mechano-sensitive channels plays a critical role in the active regulation of the pressure difference. The predictions of the model are in excellent quantitative agreement with experiments, and we propose new experiments to further test the model.