Mechanisms of Small Extracellular Vesicle-Mediated Chemotherapy-Induced Metastasis
Open Access
- Author:
- Wills, Carson
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 02, 2020
- Committee Members:
- Hong-Gang Wang, Dissertation Advisor/Co-Advisor
Hong-Gang Wang, Committee Chair/Co-Chair
Gail Lynn Matters, Committee Member
Edward Joseph Gunther, Committee Member
Rebecca Phaeton, Outside Member
Lisa M Shantz, Committee Member
Douglas B Stairs, Committee Member
Ralph Lauren Keil, Program Head/Chair - Keywords:
- Extracellular Vesicles
Breast Cancer
Neuroblastoma
Cancer Biology - Abstract:
- Chemotherapy treatment has been a mainstay of cancer therapy since the middle of the 20th century, and in addition to surgery and radiation, different combinations of chemotherapeutic drugs remain the backbone of most modern cancer treatment protocols. However, soon after the introduction of cytotoxic drugs into cancer treatment regimens, researchers discovered that some chemotherapeutic interventions had the unintended effect of decreasing primary tumor growth while promoting metastasis in both animal models and a subset of cancer patients. Over the years, different chemotherapeutic drugs have been shown to promote tumor progression through a variety of mechanisms, many of which remain poorly-defined. Therefore, an urgent need exists to elucidate the molecular mechanisms by which chemotherapy can promote metastasis in order to develop more effective treatment options for high-risk cancer patients. Recent literature suggests that one mechanism by which some chemotherapeutic drugs may accelerate tumor metastasis is through altered secretion of small extracellular vesicles (sEV), lipid nanovesicles derived from endosomal invagination that have been shown to regulate cancer progression through the horizontal transfer of biologically-active molecules, including proteins and nucleic acids. Tumor-derived sEVs are preferentially taken up in secondary organs, where they have the ability to induce vascular leakiness, alter gene expression, and promote cell chemotaxis in order to prime the pre-metastatic niche, creating a favorable environment for circulating tumor cell colonization and growth. The overarching goal of this dissertation was to utilize models of both triple-negative breast cancer and pediatric neuroblastoma to establish how chemotherapy treatment affects the secretion of sEVs from primary tumor cells, and to determine how sEVs derived from chemotherapy-treated cells regulate tumor growth and metastasis. This dissertation uncovers a novel mechanism of chemotherapy-mediated metastasis by which drug-induced upregulation of sEV secretion and sEV-associated pro-metastatic protein cargo prime the pre-metastatic niche to accelerate both breast cancer and neuroblastoma metastasis. Significantly, this research suggests that inhibition of sEV uptake in secondary organs or secretion from primary tumor cells may be promising therapeutic strategies to suppress chemotherapy-induced metastasis and improve outcomes for high-risk cancer patients.