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Identifying HIF-Independent Oncogenic Drivers in Oxygen Deficient Cells

Grubb, Treg
http://orcid.org/0000-0002-3388-758X
http://rave.ohiolink.edu/etdc/view?acc_num=case1711625555408718

Abstract Details

2024, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Oxygen is required for most multi-cellular life; however, this was not always the case. But with oxygen’s utilization in aerobic respiration, came mechanisms to deal with its scarcity (hypoxia). Indeed, the ability of cells to sense and respond to changing oxygen concentrations is critical to the physiology of all aerobic life. Responses to hypoxia are broad and organized at both organismal (hyperventilation, increased cardiac output) and cellular (reduced energy expenditure, changes in metabolism, dedifferentiation) levels. Importantly, when cellular responses go awry, they can contribute to the development of cancer. Spurred by separate reports that tumors contained regions of hypoxia and that anaerobic cells were resistant to ionizing radiation, research began to understand the clinical implications of hypoxia. We now know hypoxia associates with worse disease prognosis across solid tumors and is recognized as a critical component of the tumor microenvironment. Notably, all solid tumors contain regions of hypoxia, resultant of poor vascularization, responsible for driving many hallmarks of cancer. Hypoxia-inducible factor (HIF) transcription factors, which are understood to drive the majority of known cellular adaptations to hypoxia, are a mainstay for therapeutic development. Yet, HIF targeted interventions are insufficient to cure disease. Importantly, accumulating evidence within the last decade, has demonstrated the relevance of HIF-independent hypoxia-induced cellular adaptations to oncogenesis. Herein, our aim is to identify these mechanisms. Chapter 1 will discuss how we leveraged epigenetic and transcriptomic data to identify the SLC1A1 Asp/Glu transporter as the HIF-independent dependency in clear cell Renal Cell Carcinoma (ccRCC). Chapter 2 will discuss how we leveraged cancer lineage-specific gene dependencies to that ccRCCs are particularly dependent on the BCL-XL anti-apoptotic protein, but in a HIF-independent manner. Chapter 3 will discuss how we leveraged pharmacological screens using a stemness reporter system to identify the glucocorticoid receptor as a HIF-independent regulator of hypoxia-induced epithelial-to-mesenchymal transition in triple-negative breast cancer. Finally, chapter 4 will describe our future directions. Together, these findings add to a larger body of work demonstrating how hypoxia can drive oncogenesis independent of HIF and may explain why perturbing HIF alone does not always achieve durable anti-tumor responses.
Abhishek Chakraborty (Advisor)
Justin Lathia (Committee Chair)
Ofer Reizes (Committee Member)
Omar Mian (Committee Member)
Ruth Keri (Committee Member)
215 p.
Cellular Biology; Molecular Biology; Oncology

Recommended Citations

Citations

  • Grubb, T. (2024). Identifying HIF-Independent Oncogenic Drivers in Oxygen Deficient Cells [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1711625555408718

    APA Style (7th edition)

  • Grubb, Treg. Identifying HIF-Independent Oncogenic Drivers in Oxygen Deficient Cells. 2024. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1711625555408718.

    MLA Style (8th edition)

  • Grubb, Treg. "Identifying HIF-Independent Oncogenic Drivers in Oxygen Deficient Cells." Doctoral dissertation, Case Western Reserve University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1711625555408718

    Chicago Manual of Style (17th edition)

case1711625555408718
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© 2024, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
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