Access Type

Open Access Dissertation

Date of Award

January 2023

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Gil Mor

Abstract

Ovarian cancer induces most deaths from gynecological cancers. Patients succumb due to heavy metastatic tumor burden, which accounts for 90% of cancer related deaths and is characterized by the dissemination of malignant cells from primary tumor to secondary site(s), partaking in cancer progression. Ovarian cancer progression is an extremely demanding process that requires cancer cells to be able to survive anoikis conditions and be metabolically flexible to survive microenvironmental changes during transit to a secondary site. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) is a bi-organellar protein primarily present in the mitochondria by which it can prevent apoptosis and/or enhance mitochondrial respiration. Moreover, under stress conditions, it can act as a transcription factor to reprogram the mitochondria and promote bioenergetic efficiency. Here, we report that MNRR1 is a driver of ovarian cancer progression. We have characterized its expression and differential regulation in ovarian cancer cells. We successfully demonstrated that MNRR1 is required for a focal adhesion and extra-cellular matrix (ECM) repertoire that can support spheroid formation and promoter cytoskeleton remodeling. The loss of this function is sufficient to delay tumor growth, curtail carcinomatosis, and improve survival in a syngeneic ovarian cancer mouse model. Also, we aimed to identify early molecular pathways associated with metastasis formation in high grade serous ovarian cancer (HGSOC), including those tumors carrying somatic BRCA1 and BRCA2 mutations. Identifying gene expression profile and pathway analysis in BRCA1 and BRCA2 mutant (mt) ovarian cancer patient tumor samples compared to one another and to homologous recombinant proficient (HRP) tumors, we found that the Wnt/-catenin signaling pathway being unique to the BRCA2mt group compared to BRCA1mt or HRP. Utilizing an ID8 isogenic mouse ovarian cancer cell line harboring a mutation in Trp53, Trp53; Brca1, or Trp53; Brca2 genes, further reveal the role of differential Wnt/-catenin signaling pathway in HGSOC by which Brca2-/- confers a non-active canonical Wnt/-catenin signaling compared to Brca1-/- or Trp53-/-. Collectively, this work provides a molecular basis for new therapeutic venues in testing inhibitors of MNRR1 and the Wnt/β-catenin pathway to curtail/delay ovarian cancer tumor progression and improve the survival of patients.

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