Date of Graduation

12-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Biological Sciences

Advisor

Narasimhan Rajaram

Committee Member

Robert J. Griffin

Second Committee Member

Tameka A. Bailey

Third Committee Member

Leonard A. Harris

Fourth Committee Member

Timothy J. Muldoon

Abstract

Resistance to therapy in cancer is a major cause of poor prognosis in patients. Tumor hypoxia plays an active role in mediating treatment resistance and has been linked to metastases and metastatic potential in cancer. Our research focused on three objectives: i) To understand metabolic effects of chronic and intermittent hypoxia in murine breast cancer cells and its affiliation with metastatic potential ii) To identify the metabolic changes associated with radiation therapy in a panel of radiosensitive and radioresistant human head and neck cancer cells and iii) to monitor the changes in cell metabolism associated with gain of treatment resistance. To detect these changes, we employed optical imaging of endogenous fluorophores with two-photon excited fluorescence (TPEF) to quantify cellular metabolism. Our studies with cancer cells exposed to hypoxic stress revealed that chronic hypoxia led to changes in cellular metabolism in only poorly metastatic cancer cells while intermittent hypoxia exposure had no effect on cellular metabolism in any cancer cells. While hypoxia is known to lead to stable expression of the transcription factor – hypoxia-inducible factor (HIF-1), there are other microenvironmental stresses, such as radiation therapy that can cause activation of HIF-1. Therefore, we next investigated changes in cellular metabolism in a panel of head and neck cancer cells using TPEF and determined if the radiation-induced changes in metabolism were driven by HIF-1. Our final study involved investigating the effects of radiation therapy on cellular metabolism in a panel of isogenic cell lines that had increasing levels of radiation resistance. We found that wild type cells exhibit transformations in cellular metabolism on exposure to varied treatments while moderately resistant cells show changes in cell metabolism on exposure to HIF-1 inhibitor, YC-1 and combination of YC-1 and radiation. Conversely, there were no changes in radiation-r-resistant cells on exposure to any therapy. This present study demonstrates the ability of optical metabolic imaging to provide new insights into understanding treatment resistance in cancer cells.

Available for download on Friday, February 17, 2023

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