Date of Award
12-6-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Collective cell migration is a multiscale process, regulated by mechanosensitive proteins, adhesions between cells and with the extracellular matrix (ECM), and force propagation across length scales. The collective cell migration occurs as the cells receive the mechanical stimuli from the extracellular matrix and respond by generating forces to migrate. This behavior is widely observed in biological processes such as wound repair, angiogenesis, and pathogenic events like cancer metastasis and adipose tissue dysfunction. In these processes, cells often encounter heterogeneous topologies that disrupt and alter collective migration, yet it remains unclear how changes in matrix topology affect migration speed and cell-cell coordination. In the context of cancer metastasis, the presence of heterogeneous subpopulations within collectively migrating cells introduces additional complexity in understanding invasion and metastasis. The distinct roles of various cell types in generating protrusions to invade and in remodeling collagen, warrant further investigation. This dissertation aims to address these ambiguities and provide a comprehensive understanding of the factors that influence collective cell migration. Chapter 2 studies how the matrix obstructions affect the leader and follower cells in collective migrating epithelial monolayers. Using microfabricated Polydimethylsiloxane (PDMS) that has obstructions on the migrating surface in different orientation, density, and geometry, the cellular response and disorder are measured in meso- and micro- length scale. The study highlights that healthy cell populations with the optimal balance between cell-cell cohesiveness and cellular protrusions are more sensitive to obstructions compared to the aggressive and dysfunctional cells composed of either hyperactive leader or unruffled follower cells. Chapter 3 explores the tumor microenvironment, where heterogeneous cell subpopulations contribute to the complexity of understanding collective cell migration. Spheroids consisting of either tumor cells (4T1s), cancer-associated fibroblasts (CAFs), or a co-culture of 4T1s and CAFs are embedded within a three-dimensional collagen matrix. This study highlights the critical need to distinguish between cellular subtypes and their specific functions, as these cells, individually or co-dependently, affect both net invasion and collagen deformation. In order to effectively target the tumor invasion, the deeper functional understanding of cellular protrusions or the contractility in specific collagen densities is necessary.
Language
English (en)
Chair
Amit Pathak
Committee Members
Alexandra Rutz; Chao Zhou; Gregory Longmore; Nathaniel Huebsch