Lipid metabolism: a mediator of phenotypic transformation in ovarian cancer

Metastatic and chemoresistant disease remains a challenge of ovarian cancer (OVCA), and has been proposed to involve metabolic reprogramming in metastatic and tumour-initiating cells (TIC). Metabolic adaptation to an adipose-rich tumour microenvironment, such as in OVCA metastasis, likely involves crosstalk with adipocytes and upregulated mitochondrial respiration and fatty acid (FA) metabolism. However, the role of this crosstalk and related metabolic alterations in OVCA progression remains poorly understood. Gene expression and enrichment analysis showed that, compared to primary ovarian tumours, omental metastases exhibited upregulated expression of lipid metabolic genes, and enrichment of cellular motility/invasion, proliferation and survival pathways. Additionally, in omental metastases, expression of lipid metabolic genes FABP4, GPD1, and CIDEA correlated with cell proliferation genes, and high expression associated with better survival. The role of PGC-1, a master regulator of FA metabolism and mito-biogenesis, was investigated in-vitro in an OVCA cell line, SKOV-3, and a cisplatin-selected sub-line, SKOV-3-R, representing tumour progression with TIC properties and lacking in PGC-1α expression. Results showed that, in a PGC-1-independent manner, SKOV-3-R cells increased FA metabolic capabilities evidenced by increased CD36 expression, greater FA-linked OXPHOS coupling efficiency, and unaffected ATP levels in response to the addition of oleic acid and glycolysis inhibition. Although PGC-1α expression did not associate with chemoresistance in the gene expression studies, knockdown of PGC-1α in parental SKOV-3-P cells resulted in increased cisplatin resistance, mitochondrial fragmentation and peri-nuclear clustering, but did not increase TIC-marker expression. Lastly, culturing cells under high- and low glucose conditions with or without oleic acid induced different patterns of mito-organization and PGC-1α levels, indicating the responsiveness of these metabolic properties to the nutrient environment and emphasizing the need for the use of physiologically relevant nutrient conditions when investigating metabolic adaptation in cancer cells. Overall, these data have contributed to the understanding of metabolism in OVCA progression.