Rgnef promotes ovarian tumor progression and confers protection from oxidative stress
- Author(s): Kleinschmidt, Elizabeth
- Advisor(s): Schlaepfer, David D
- et al.
Ovarian cancer is the most deadly gynecological malignancy, with few treatment options. High mortality is largely due to late diagnosis after the disease has metastasized. Ovarian tumor cells typically metastasize by detachment from the primary tumor into the peritoneal cavity. Aggressive tumor cells form multicellular spheroids, which attach and invade at distant sites. Preventing tumor spheroid survival, attachment, and invasion may provide therapeutic benefit.
Rgnef is a Rho guanine nucleotide exchange factor that canonically activates Rho GTPases, key coordinators of adhesion, migration, and contractility. Rgnef is activated downstream of integrin engagement with the extracellular matrix, and also binds directly to focal adhesion kinase (FAK). While Rgnef has been shown to promote colon carcinoma growth and invasiveness, the role of Rgnef in other types of cancer is unknown. In this thesis, I explore the role of Rgnef in ovarian carcinoma.
In Chapter 2, I demonstrate that Rgnef is overexpressed in late-stage serous ovarian cancer, and that high Rgnef expression corresponds to poor prognosis in late-stage patients. I use a genetically engineered mouse model and murine ovarian cancer cell lines to investigate the role of Rgnef in ovarian cancer tumor progression, demonstrating that Rgnef promotes both primary ovarian tumor formation and metastatic dissemination. Furthermore, I find that Rgnef is required for anchorage-independent spheroid growth. Finally, I reveal a novel role for Rgnef in promoting an NF-kB-mediated antioxidant gene signature, which may protect cells from reactive oxygen species induced in anchorage-independent conditions. In Chapter 3, I characterize a novel aggressive murine cell line that models human ovarian cancer. In Chapter 4, I explore how the interaction between Rgnef and FAK promotes growth and contractility when attached to extracellular matrix.