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Open Access Dissertation
Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
Biochemical and Biomolecular Engineering | Biological Engineering | Biomaterials | Molecular, Cellular, and Tissue Engineering
Breast cancer is plagued by two key clinical challenges; drug resistance and metastasis. Most work to date probes these events on an extremely rigid plastic surface, which recapitulates few aspects of these processes in humans. A malignant cell first resides in breast tissue, then likely travels to the bone, brain, liver, or lung, each of which has a distinct mechanical and biochemical profile. Cells transmit mechanical forces into intracellular tension and biochemical signaling events, and here we hypothesize that this mechanotransduction influences drug response, growth, and migration.
To probe the impact of extracellular matrix on drug resistance, we defined a set of biomaterials that allowed us to independently tune stiffness, dimensionality, and cell-cell contacts. We screened response to therapeutics across these material systems, and found that these environments increased resistance to targeted, but not cytotoxic, therapies compared to traditional screening on plastic. A systems biology analysis was applied to signaling data across platforms to identify MEK phosphorylation as a key driver of resistance. Comparing robust biomaterial screening to traditional plastic, we identified the role individual features of the tumor microenvironment in adaptive resistance.
The drug response study systematically varied several biomaterial parameters, but the remainder of this work isolated tissue stiffness as a driving force behind metastasis. Here we identified two mechanosensitive proteins that are at least partially responsible for adhesion and motility in breast cancer cells. On soft matrices, integrin α6 and laminin production mimic the aggressive cell behavior induced by epidermal growth factor (EGF). Integrin α6 and the EGF receptor then coordinate to activate calpain 2, which is necessary for migration to distant sites. However, cells likely reside at a metastatic site for long times, so we probed the effect of extended mechanical cues on cell behavior. On biomaterials, cells are selected for phenotypes that mirror primary tumor cells that have never been grown on plastic. This work shows that cells retain memory of their previous mechanical environment, even after being re-challenged with culture in very rigid environments. Using biomaterials, we captured physiological aspects of drug resistance and metastasis, to better understand and ultimately treat breast cancer.
Schwartz, Alyssa, "BIOPHYSICAL FEATURES OF THE EXTRACELLULAR MATRIX DIRECT BREAST CANCER METASTASIS" (2018). Doctoral Dissertations. 1458.