2026 Theses Doctoral

Nuclei-Driven Jamming Transitions in Confluent Cellular Systems

Yu, Karen

The nucleus has been found to play important roles in cell migration. Generally, the nucleus has been used as an indicator of cell mobility, with elongated mobile cells containing elongated nuclei. The nucleus can also determine cell invasive capacity, as this large and stiff organelle can be a bottleneck to migration in dense environments. Additionally, recent findings have shown that the nucleus acts not only as a passive compartment the cell must translocate, but an important mechanosensor allowing the cell to deform and move through confined spaces. Here, we elucidate the role of the nucleus in bulk fluidity of multicellular spheroids and both bulk and local fluidity of simulated cells within a novel Cellular Potts Model that includes both an internal nuclear compartment and an underlying actin-based activity lattice.

In multicellular spheroid coalescence, we find that a small change in epithelial-mesenchymal transition status, corresponding to a significant change in nuclear occupancy, results in full traversal of the solid-to-fluid continuum – a finding we also recapitulate in simulations. We propose that stiff nuclei impede fluid-like behavior and thus find that by softening nuclei in experiments, fluidization of an otherwise solid-like system occurs. We also employ both homotypic and heterotypic systems to carefully traverse jamming phase spaces.

Through using heterotypic systems, we find that cells are affected by their neighbors, with both cell phenotype and behavior being altered by characteristics of surrounding cells. Within the simulations, we propose that this emerges from the interplay of the nucleus with the surrounding actin-inspired activity field, creating a mechanosensitive nucleus, reminiscent of that identified in experiments. In sum, we find that across both experiments and simulations, the ability of the nucleus to translocate, determined by nuclear occupancy and nuclear deformability of a given cell and its neighbors, dictates fluidity.