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|Title:||Mechanical Regulation of Autophagy, Chemoresistance and Genomic Instability|
|Advisors:||Nelson, Celeste M|
|Contributors:||Chemical and Biological Engineering Department|
|Publisher:||Princeton, NJ : Princeton University|
|Abstract:||The mechanical properties of the tumor microenvironment influence breast cancer progression by regulating cell proliferation, invasion and dissemination. Stiffening of the extracellular matrix (ECM), a defining feature of breast tumors, promotes cancer cell division, genomic instability and metastasis. During metastasis, the dissemination of breast cancer cells from a primary tumor to secondary sites with different mechanical properties could lead to prolonged growth arrest, or dormancy, and resistance to conventional hormone- and chemotherapy. In line with this, breast cancer relapse is often detected in tissues that are softer than the normal mammary gland or the primary breast tumor, such as the bone marrow, the brain, and the lung. Although metastasis is the main cause of death from cancer, the microenvironmental factors that influence resistance to therapy and the duration of dormancy are largely unknown. This dissertation explores how the stiffness of the microenvironment at secondary sites regulates tumor dormancy and the response of breast cancer cells to hormone- and chemotherapy. We show that in soft microenvironments reminiscent of common metastatic sites, breast cancer cells resist the effects of the estrogen receptor modulator tamoxifen by increasing autophagy and decreasing expression of estrogen receptor-α. Consistently, we demonstrate that pharmacologic inhibition or genetic downregulation of autophagy sensitizes breast cancer cells to tamoxifen on soft substrata. Further, we find that stimulating cell-ECM adhesion by ectopically expressing integrin-linked kinase is sufficient to decrease autophagy on soft substrata. We then investigate the mechanisms by which stiff microenvironments regulate genomic instability in healthy mammary epithelial and breast cancer cells. We demonstrate that TGFβ-induced epithelial to mesenchymal transition and ECM stiffening promote multinucleation, a marker of aneuploidy, and that mitotic failures on stiff microenvironments correlate highly with DNA damage. Altogether, our data show that the crosstalk between cancer cells and their mechanical microenvironment regulates therapeutic outcome, long-term survival, and genomic integrity.|
|Alternate format:||The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog: catalog.princeton.edu|
|Type of Material:||Academic dissertations (Ph.D.)|
|Appears in Collections:||Chemical and Biological Engineering|
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