Date of Award
Summer 9-12-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Cells constantly interact with and interpret their environment as they migrate, a process integral to an array of vital physiological events within the body. One such form of cellular migration that is of particular significance is collective migration, a coordinated and group-based movement that is central to various biological processes such as embryogenesis, tissue repair, and cancer metastasis. As these cells navigate through the body, they receive and process a wide array of inputs and cues from their surroundings that guide their direction and velocity. These cues are not simply instantaneous or immediate, they span across time and length, presenting a dynamic and intricate web of interaction that cells must decode. These inputs can be cellular in the form of individual cell polarization or 'mechanical memory,' whereby cells integrate the information they receive over time. In addition, cells also sense and respond to cues along the length scale of their migration, a key example being the influence of extracellular matrix (ECM) properties. The ECM serves as a physical scaffold for cells and imparts information about the tissue's structural composition, rigidity, and biochemistry, thereby playing a significant role in modulating cellular migration. The exploration of. Here, I present the influence of these multi-dimensional interactions and how cells utilize them during collective migration. Chapter 2 explores the influence of individual cells' repolarization dynamics in regulating the collective migration of heterogeneous cell populations. Using a vertex-based model that encapsulates individual cell behavior and experimental observations, we identify long repolarization intervals as a characteristic of "leader" cells, contributing to more effective collective migration. Our findings reveal how variations in repolarization dynamics can significantly alter the migration modes of cell populations, providing essential insights into collective cell migration in disease and development. Chapter 3 delves into modeling collective migration in heterogenous breast cancer organoids, focusing on the formation and localization of leader cells in breast tumors. Through computational models developed from live videos of primary mouse and human breast tumor organoids, we identify the need for leader cells to generate high protrusive forces and to overcome extracellular matrix (ECM) resistance at the leading edge. This work highlights the role of a CDH3+ subpopulation in controlling cell protrusion dynamics, underpinning the importance of their interaction with the microenvironment in directing collective migration. The potential therapeutic implications of understanding leader cell heterogeneity in tumor progression and metastatic disease are also addressed. Chapter 4 to 6 are dedicated to examining the implications of the ECM, a pivotal component of the cellular microenvironment. Chapter 4 explores role of ECM stiffness from a timescale perspective, and how cells are able to remember these stiffness cues, aka mechanical memory, even after moving away from the previous cues. We model mechanical memory in cells by integrating transcriptional activity and epigenetic plasticity with conventional models of mechanotransduction, the process by which cells sense their environment. We explore the role of varying priming and memory factor kinetics on kinetics of memory. These insights are validated using experimental findings of memory storage and decay in epithelial cell migration and stem cell differentiation, offering a deeper understanding of cellular memory. Chapter 5 delves into role of ECM dimensionality, causing mechanically primed cells to transfer memory to fibrous matrices, enabling invasion across environments of varying stiffness and dimensionality. Using a lattice-based computational model, we demonstrate that stiff-primed cells generate higher forces to remodel collagen fibers and enhance invasion, thus overcoming the challenges of fibrous environments. Notably, this cell-to-matrix transfer of memory was found to play a crucial role in invasive processes across mechanically distinct environments, offering potential implications for understanding cellular behavior in cancer, fibrosis, and aging. Chapter 6 explores the intriguing process of 'depth mechanosensing' in layered matrices, which allows cancer cells to sense and migrate in response to deeper, stiffer substrates, unlike healthy epithelial cells. By utilizing layered collagen-polyacrylamide gel systems and energy minimization modeling, we demonstrate how cell-matrix polarity, formed by polarized cellular protrusions and contractility leading to polarized ECM, enable this cell-type-dependent migration. Disruptions to this polarity, through various means, eliminate this depth-mechanosensitive migration, highlighting the crucial crosstalk between cellular and extracellular polarity in facilitating this cell migration mechanism. Overall, this dissertation significantly enhances our understanding of collective migration, particularly the role of cellular and ECM cues. By utilizing a combination of computational models and experimental observations, we have been able to elucidate the mechanisms behind these multi-dimensional interactions. Our findings offer new insights into cellular behavior in development, disease progression, and tissue repair.
Language
English (en)
Chair
Amit Pathak