Advisory Committee Chair
Mythreye Kartikeyan
Advisory Committee Members
Rebecca C Arend
Susan Bellis
Vivek Nanda
Sooryanarayana Varambally
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Ovarian cancer is the second most common and deadliest cancer of the female reproductive system affecting women in the United States and worldwide. The poor survival outcome seen in ovarian cancer is attributed to the subtleness of its early-stage symptoms, resulting in a majority of patients at initial diagnosis presenting with an advanced-stage disease with metastasis to other parts of the body. Hence, there is an urgent need to better understand the molecular etiology of metastasis to help develop effective therapeutic options and improve clinical outcomes in ovarian cancer patients. Ovarian cancer, an intra-abdominal cancer, most preferably undergoes metastasis via peritoneal spread which involves cell-matrix detachment and aggregate formation in the peritoneal cavity, a phenomenon referred to as anchorage-independence. Normal cell-matrix detachment triggers a programmed cell death response called anoikis, and thus, ovarian cancer cells acquire anoikis resistance to enable survival under detached conditions for metastasis. The ovarian cancer tumor environment is enriched with cytokines especially members of the transforming growth factor-beta (TGF-β), which act as key regulators of iv cell survival and anoikis resistance during metastasis. We have found a significant dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin, and their downstream SMAD effectors in the regulation of anchorage-independent tumor cell survival in ovarian cancer. Gene expression profiling uncovered SOX2 as a central signaling node regulated in an opposing manner by anoikis-promoting BMP2, 4, and 9, and anoikis-suppressing TGF-β and activin A. Our findings implicate the use of a subset of BMPs as a therapeutic strategy in ovarian cancer and demonstrate a critical role of context-specific SOX2 regulation in controlling anchorage-independent survival and metastasis in ovarian cancer.
Recommended Citation
Shonibare, Zainab, "Molecular Mechanism and Impact of SOX2 Regulation by the Transforming Growth Factor-ß Members in Ovarian Cancer Survival and Metastasis" (2022). All ETDs from UAB. 335.
https://digitalcommons.library.uab.edu/etd-collection/335