Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Dr. Trevor Shepherd

Abstract

Epithelial ovarian cancer (EOC) has a unique mode of metastasis, where upon shedding from the primary tumor, cells form spheroids and spread through the peritoneal cavity. There is a need to elucidate pathways driving spheroid formation to identify novel therapeutic targets. We previously showed that LKB1 is required for EOC metastasis. Using multiplex inhibitor bead-mass spectrometry, we identified NUAK1 as a top LKB1 substrate candidate. We confirmed LKB1 maintains NUAK1 phosphorylation and expression. NUAK1KO cells had lower cell adhesion and generated spheroids with reduced integrity. We identified a cell attachment pathway that was enriched in parental compared with NUAK1KO spheroids. The FN1 gene, encoding fibronectin, exhibited the greatest differential expression in NUAK1KO spheroids. Parental spheroids have enhanced fibronectin expression, which was undetectable in NUAK1KO spheroids. Treatment of NUAK1KO cells with fibronectin restored a compact spheroid phenotype. We have identified a novel mechanism where NUAK1 promotes spheroid formation through fibronectin deposition.

Summary for Lay Audience

Ovarian cancer is the most lethal gynecologic malignancy and is characterized by early and rapid metastasis. Most women are diagnosed with advanced-stage disease with a 5- year survival rate of only 29%. The standard treatment plan for patients with late-stage ovarian cancer is maximal surgical cytoreduction with adjuvant chemotherapy of carboplatin and paclitaxel. However, the majority of patients will eventually develop disease recurrence and resistance to chemotherapy. Therefore, there is a need to develop novel therapeutic strategies to impede ovarian cancer metastasis. Our group previously showed that liver kinase B1 (LKB1) is critical for ovarian cancer metastasis. We present evidence that NUAK1 is likely a key substrate enabling LKB1 to drive ovarian cancer metastasis through regulating ovarian cancer cell adhesion and spheroid integrity. Mechanistically, NUAK1 regulates fibronectin along with a network of adhesion molecules to control spheroid formation. We have identified a novel function for the LKB1 target NUAK1 in promoting efficient ovarian cancer metastasis.

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