Author ORCID Identifier
https://orcid.org/0000-0003-1155-8707
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Priscilla Hwang
Second Advisor
Rebecca Heise
Third Advisor
Christopher Lemmon
Fourth Advisor
Paula Bos
Fifth Advisor
Swadesh Das
Abstract
In breast cancer metastasis, cancer cells migrate as a group, termed collective migration. In migrating breast tumors, cytokeratin-14 positive (K14+) leader cells polarize from their random position within the tumor cluster and direct collective migration in response to tumor microenvironment cues. In the breast tumor microenvironment, stromal cells such as cancer-associated fibroblasts or immune cells are believed to impact breast tumor dissemination through extracellular matrix remodeling and fiber alignment. However, the effect of the role of the local mechanical environment on K14 leader cell polarization and collective migration is not well understood. The central objective of this dissertation was to understand how dynamic ECM changes, specifically matrix fiber orientation, affects leader cell mechanics in collective migration. Our central hypothesis was leader cells use CDH3 to generate traction forces and protrusions to promote collective migration in response to the mechanical cue of fiber alignment. To study this, we first studied collective migration in the presence of aligned collagen fibers using two biologically relevant models and a novel 3D microphysiological system to mimic the key mechanical features of the tumor microenvironment. Then we investigated the mechanical response of leader cells as mediated by CDH3 by measuring 2D traction forces and quantifying focal adhesions. Additionally, we begin to probe a mechanosignaling pathway responsible for leader cell protrusions and traction forces. This work contributes to our understanding of the complex process of metastasis and may aide in the design of novel anti-cancer therapies to prevent tumor dissemination.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-13-2024