Date of Award

Spring 5-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Angiogenesis is a critical determinant of neoplastic growth and metastatic spread. As such, anti-angiogenic approaches have long been tried to throttle down tumor progression. However, current anti-angiogenic treatments so far have produced modest clinical benefits. Further in-depth research has provided rationales behind these disappointing and apparent perplexing clinical outcomes. It is now established that VEGF (vascular endothelial growth factor) and other prominent current angiogenic targets are neither specific to the vascular system nor the pathological conditions explaining the sub-optimal angiogenic control following the existing treatments. This suggests that anti-angiogenesis could still be a viable strategy for cancer patients should there are targets exclusive for tumor angiogenesis. The goal for my Ph.D. dissertation has been to identify novel angiogenic targets and their mechanism(s) of action in controlling tumor angiogenesis and growth.In aim 1, I have demonstrated that ETS transcription factor Etv2, which is critical for the endothelial and hematopoietic development exclusively in the developmental phase but stays silent in the adult phase, is reactivated in the endothelium of both the human cancers and mouse models of tumors. Etv2 deficiency renders the tumor vasculature similar to normal vessels and reduces tumor growth. Oxidative stress in the tumor environment is likely the driver to initiate Etv2 expression in the endothelial cells. Despite being a promising and exclusive target for tumor angiogenesis, it is challenging to utilize Etv2 as a therapeutic target because transcription factors are generally considered non-druggable. To address this, in aim 2, I have identified Myct1, a direct downstream target of Etv2, as a novel and endothelial-specific angiogenic gene. MYCT1 is a cell membrane-localized protein that makes it targetable by antibody-mediated approaches. Myct1 deficient endothelial cells lose migratory angiogenic phenotype in vitro and demonstrate normalized vascular functions in the in vivo tumor models. Moreover, Myct1 deficiency promotes an anti-tumor immune microenvironment that leads to limited tumor growth. Combined Myct1 targeting drastically improves the outcome of the anti-PD1 immunotherapy in the mouse models. The data presented in this dissertation have collectively identified the Etv2-Myct1 axis as a novel endothelial-specific regulator of tumor angiogenesis and tumor immunity. Myct1-targeted anti-angiogenic treatment could provide significantly better outcomes compared to the existing treatments, especially in combination with the immune checkpoint blockade immunotherapy.

Language

English (en)

Chair and Committee

Kyunghee Choi

Committee Members

Joshua Rubin, Katherine Weilbaecher, David Ornitz, Paul Allen,

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