Date of Award

Summer 2022

Document Type

Open Access Dissertation

Department

Chemistry and Biochemistry

First Advisor

Mythreye Karthikeyan

Second Advisor

Caryn Outten

Abstract

Inhibins are heterodimeric ligands within the TGFβ superfamily, comprised of an α-subunit (INHA) and a β-subunit (either INHBA or INHBB) with emergent roles in cancer. Inhibins are biomarkers of disease burden and prognosis in a subset of cancers and utilize the coreceptors betaglycan (TGFBR3) and endoglin (ENG) for physiological or pathological outcomes. Previously, we found inhibin promotes angiogenesis in ovarian cancer however no mechanism of regulation for inhibin expression in cancer has been established. Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. However, toxicities and resistance to anti-angiogenics can limit their use making identification of new targets vital. Inhibin is a particularly interesting target for anti-angiogenic therapy within ovarian cancer, as expression is abrogated in healthy post-menopausal women when compared to premenopausal women, but markedly elevated in those with ovarian malignancies. Of note, postmenopausal women make up the majority of ovarian cancer diagnoses, with an average age of diagnosis of sixty-two. In these patients, targeting inhibin may not present the toxicities associated with other anti-angiogenic therapies. Here, we look to establish a mechanism of regulation of inhibin in cancer, define inhibin as a therapeutic target, and assess the prognostic value of inhibin and its network of receptors (endoglin and betaglycan) in a pan-cancer analysis. These studies reveal that inhibin, specifically INHA, is regulated by hypoxia through the transcription factor HIF-1. Hypoxia regulated inhibin promotes tumor growth, endothelial cell invasion and permeability. Targeting inhibin in vivo through knockdown and anti-inhibin strategies robustly reduces permeability in vivo and alters the balance of pro and anti-angiogenic mechanisms resulting in vascular normalization. A pan-cancer, bioinformatics analysis revealed gene alterations and identified cancer cell lines and types that were most dependent and impacted by members of the inhibin network. Expression of these markers was predictive of both survival and response to chemotherapeutics. Using cancer types where inhibin, endoglin and betaglycan were predictive of survival, gene signature analysis was performed to obtain a highly accurate prognostic model and to determine correlated pathways. Ultimately, these findings provide new insights into the therapeutic potential of inhibin as an anti-angiogenic target in ovarian cancer and shed light on the importance of the inhibin-endoglinbetaglycan network in other cancer types as well.

Rights

© 2022, Ben Allen Horst

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