Elucidating the mechanism of NUAK1 function in Ovarian Cancer Metastasis
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.