Abstract

Collective cell migration governs wound healing, tissue regeneration, and even cancer metastasis. Cells in a collective must communicate with their neighbors and the matrix to adapt to their microenvironment, regulated by large-scale cell-cell coupling, emergence of leader-follower phenotype, and supracellular actin organization. This thesis investigates the roles of intracellular and intercellular communication in collective cell migration. In the first aim, we block the intracellular communication by disturbing the LINC (linker of nucleoskeleton and cytoskeleton) complex in mammary epithelial cells. The LINC complex physically bridges the cytoskeleton to the nuclear components. We observed that LINC-disrupted cells had a slower migration speed and impaired mechanosensitivity compared to their wild-type counterparts. We speculate that loss of tension from LINC disruption leads to cellular softening, causing smaller cells and more crowded epithelial monolayers. Additionally, these LINC disrupted cells had lower non-muscle myosin IIA and pMLC levels, along with an increase in vinculin. In the second aim, we use osmolarity to stimulate intercellular communication. We found that chronic exposure to mild hypoosmotic condition dramatically increases migration speed in mammary epithelial monolayers. This osmolarity-enhanced migration further increases on stiffer matrices, driven by actin polymerization, and independent of Arp2/3 mediated branching. We found that SWELL/PI3K signaling aids directionality for migration. Loss of cell-cell adhesions is important to sustain this hyperactive migration, enabling followers to contribute towards net migration. The two aims describe contrasting perturbations – blocking intracellular communication produces a global decrease in migration, while modulating intercellular communication produces a global increase, both achieved by altering the underlying subcellular communication machinery. Together, these findings establish nuclear–cytoskeletal coupling and osmolarity as distinct levers on the same emergent system, with implications for understanding both normal tissue mechanics and pathological contexts where these communication machineries are compromised.

Committee Chair

Amit Pathak

Committee Members

Eynav Klechevsky; Guy Genin; Jessica Wagenseil; Matthew Bersi

Degree

Doctor of Philosophy (PhD)

Author's Department

Mechanical Engineering & Materials Science

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

7-23-2026

Language

English (en)

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Available for download on Saturday, July 22, 2028

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