Author ORCID Identifier

https://orcid.org/0000-0003-3080-8484

Semester

Fall

Date of Graduation

2022

Document Type

Thesis

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Lori Hazlehurst

Committee Co-Chair

Karen Martin

Committee Member

Karen Martin

Committee Member

Elena Pugacheva

Committee Member

Mike Schaller

Committee Member

Sijin Wen

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a cancer originating from the epithelial lining of the oral cavity, larynx, and pharynx. HNSCC is associated with extensive locoregional invasion and tissue destruction. Invasive processes underlying HNSCC contribute to poor prognosis and decreased quality of life. Amplification of chromosome 11q13 is the most common DNA aberration in human papilloma virus negative (HPV-) HNSCC. This region includes various genes known to drive tumor progression. CORO1B (coronin 1B) flanks the core 11q13 region and is amplified in 7-14% of HNSCC. Coronin 1B is essential for mesenchymal cell motility by promoting turnover of the cortical filamentous (F)-actin cytoskeleton. Study 1 of this dissertation seeks to determine the impact of CORO1B amplification and protein overexpression in driving HNSCC progression through use of patient data, in vitro invasion assays, and in vivo experiments. CORO1B amplification and overexpression in patient tumors correlate with enhanced patient decline. Coronin 1B is also a vital component for matrix metalloproteinase (MMP)-mediated invadopodia function and extracellular matrix degradation, enhances 3D invasion, and potentially governs intratumor contractility and proliferation. Identification of coronin 1B overexpression as an important mediator in promoting HNSCC invasive processes may define a novel aggressive subset of locoregional involved HNSCC that would benefit from enhanced clinical intervention. Tumor cell invasion is reliant on matrix metalloproteinase activity for remodeling the ECM. Previous clinical targeting of MMPs has been unsuccessful due to deleterious side effects and lack of clinical benefit. MMP9 is overexpressed in HNSCC and other cancers. Andecaliximab (ADX) is a second-generation anti-MM9 monoclonal antibody that shows high specificity and is well-tolerated in clinical trials. Study 2 evaluates the effectiveness of andecaliximab as an anti-invasive therapy in pre-clinical models of HNSCC. ADX fails to decrease gelatin degradation or 3D tumor cell invasion as a monotherapy. Additional work combining ADX with other current or emerging therapeutics against HNSCC oncogenic targets may provide clinical benefit in the future.

Embargo Reason

Publication Pending

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