Research

This project used a two-dimensional mathematical model of mammalian cell migration, building upon a previous one-dimensional model. The model incorporates actin polymerization and depolymerization, explicitly including monomeric actin to improve accuracy in predicting cell morphology and velocity. We compared the predictions of both models and highlighted the two-dimensional model's superior ability to capture cell shape evolution and transverse variations in actin dynamics. We quantified how varying parameters, such as actin depolymerization rates and polymerization distribution, influence cell morphology, velocity, and actin distribution within the cell. The findings reveal a crucial link between microscopic actin dynamics and macroscopic cell behavior.

This project used a mathematical model to study how cell migration is influenced by the interplay of mechanics, electrochemistry, and pH regulation. The model incorporates various ion channels, exchangers, and pumps. It examined how their polarization, coupled with extracellular pH and electric field gradients, affects intracellular ion distribution, pH, electric potential, and water flux. A key finding is the crucial role of the sodium-hydrogen exchanger and its interaction with F-actin in driving cell movement. The study also highlights the importance of actin dynamics and its coupling with pH in modulating cell migration. The results provide insights into cell migration mechanisms with potential medical implications.

This project investigates the interplay between cytoskeletal dynamics, calcium signaling, and ion fluxes in regulating cell volume, focusing on a secondary volume increase (SVI) observed in normal cells but absent in cancer cells after hypotonic stress. We identified a mechanosensitive pathway involving Piezo1, actomyosin remodeling, ezrin, and NHE1, leading to SVI and impacting gene expression and cell proliferation. A computational model supports these findings, highlighting the roles of NHE1 and NKA in volume regulation. Disrupting the actomyosin network or inhibiting key proteins eliminates SVI, demonstrating its dependence on cytoskeletal activity. The results suggest that SVI, a process largely absent in cancer cells, plays a significant role in suppressing cell growth.

This project studies how fluid forces affect cell migration within confined spaces. Using microfluidic devices, we demonstrate that tight confinement causes cells to move upstream (against the flow) in response to pressure, a phenomenon less pronounced with chemotaxis or high resistance. This upstream migration involves cytoskeletal changes, including actin polymerization and myosin II redistribution, along with calcium and NHE1 activation. Conversely, cells with low lamin A/C levels exhibit reduced mechanosensitivity and migrate downstream, potentially aiding cancer cell escape from high-pressure tumors. The study integrates experimental findings with a biophysical model to explain the observed cellular mechanisms.

This project demonstrates that increased extracellular fluid viscosity, a physical cue, unexpectedly enhances cancer cell migration and metastasis. Elevated viscosity triggers a cascade of cellular events: it induces actin network reorganization via the ARP2/3 complex, leading to NHE1 polarization, cell swelling, TRPV4 activation, and ultimately, increased RHOA-dependent contractility. This heightened motility is observed in various cell types in vitro and translates to increased extravasation and lung colonization in vivo. Furthermore, cells develop a "viscous memory," retaining enhanced migratory capacity even after viscosity is reduced, a phenomenon linked to TRPV4 and the Hippo pathway.