Kevin Tabury

Date of Award

Summer 2022

Document Type

Open Access Dissertation

Department

Biomedical Engineering

First Advisor

Mythreye Karthikeyan

Second Advisor

Tarek Shazly

Abstract

Gynecological cancers, ovarian and endometrial cancer, are still leading causes of cancer-related death in women worldwide. Early detection methods as well as treatment resistance remain a challenge. Long non-coding RNAs (lncRNAs) are emerging as therapeutic targets with diagnostic and prognostic potential with lncRNA PVT1 being one of them.

Here I test and demonstrate the role of PVT1 in ovarian cancer growth and metastasis. PVT1 is amplified and overexpressed in ovarian cancer and has predictive value for survival and response to targeted therapeutics. We find that expression of PVT1 is regulated by tumor cells in response to cellular stress, particularly loss of cell-cell contacts and changes in matrix rigidity occurring in a YAP1-dependent manner. Induction of PVT1 promotes tumor cell survival, growth, and migration. Conversely, reducing PVT1 levels robustly abrogates metastatic behavior and tumor cell dissemination in cell lines and syngeneic transplantation models in vivo. We find that reducing PVT1 causes widespread changes in the transcriptome leading to alterations in cellular stress response and metabolic pathways including doxorubicin metabolism, which impacts chemo sensitivity in ovarian cancer. We further investigated the role of PVT1 DNA alterations and RNA expression in endometrial cancer. We find that PVT1 has predictive value for survival and potentially treatment response. High PVT1 RNA expression combined with PVT1 amplification results in poor patient survival, is characterized by an enrichment of cell cycle progression through E2F and MYC target genes and corresponds to type 2 endometrial cancer. On the other hand, PVT1 diploid patients have the best survival without consideration of PVT1 RNA expression and correspond to type 1 endometrial cancer. PVT1 low RNA expression combined with PVT1 diploid is characterized by an enrichment of the estrogen signaling pathway, suggesting PVT1 as a good candidate to explore for response to hormonal therapy.

Together, these findings implicate PVT1 as a promising therapeutic target as well as a potential biomarker of survival and treatment response in ovarian and endometrial cancer.

Rights

© 2022, Kevin Tabury

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