UBC Theses and Dissertations
Investigating intrinsic and extrinsic factors that regulate cancer cell motility Decotret, Lisa Rachelle
Mechanisms of cellular motility are highly conserved and regulate many physiological processes including embryonic development, wound healing, and angiogenesis. Cancer cells can exploit normal mechanisms of cellular motility to facilitate invasion and metastasis, the process by which cancer cells disseminate to distant organs. Invasion can be triggered by a host of intrinsic and extrinsic factors, many of which remain unknown. Here, I investigate the role of one intrinsic factor (receptor-type protein tyrosine phosphatase alpha) and one extrinsic factor (ionizing radiation) in facilitating cancer cell invasion. Receptor-type protein tyrosine phosphatase alpha (PTPα is a widely expressed transmembrane-bound protein that has been implicated in integrin signaling, focal adhesion formation, and normal cell migration. During normal cell migration, cells use focal adhesions to facilitate cycles of cell adhesion to, and release from, the extracellular matrix (ECM). Focal adhesion structures bear resemblance to invadopodia, which are dynamic actin-based protrusions that form on the plasma membrane of cancer cells. In this study, I hypothesized that PTPα promotes invadopodia-mediated triple-negative breast cancer (TNBC) cell invasion. My work involving the depletion of PTPα in TNBC reveals PTPα as a regulator of ECM degradation and invasion in vitro and in vivo. My studies suggest that PTPα is an intrinsic regulator of TNBC cell invasion. Radiation therapy is among the most common treatments for cancer. While radiation is an effective treatment option, there have been reports showing the surviving fraction of cells may exhibit increased invasiveness. Since the precise mechanisms that modulate ionizing radiation (IR)-induced invasion remain largely unknown, the goal of this study was to investigate the role of IR in upregulating key signaling mechanisms associated with invadopodia activity. Our studies revealed IR upregulates a key invadopodium protein, TKS5, expression while decreasing Glioblastoma multiforme (GBM) cell invasion in vitro, suggesting GBM cells invade independently of invadopodia. I then developed an ex vivo brain slice invasion assay to investigate mechanisms of GBM cell invasion into brain tissue. Using this model, I found a subset of GBM spheroids exhibited increased invasion post-irradiation. These studies suggest IR is a potential extrinsic regulator of GBM invasion when cells are within the brain microenvironment.
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