Omentin-induced metabolic reprogramming in the omental microenvironment suppresses high-grade serous ovarian cancer progression

Advanced-stage high-grade serous ovarian cancer (HGSC) metastasizes preferentially to the omentum, which is a well-vascularized fold of peritoneal tissue covered by mesothelial cells and a major site of intra-abdominal fat accumulation. We report that HGSC altered the gene expression of mesothelial cells in visceral adipose tissue and significantly downregulated the expression of a novel adipokine, omentin. Circulating levels of omentin are significantly lower in HGSC patients than those in body mass index-matched healthy women. High levels of serum omentin in HGSC patients were associated with longer overall survival time. These findings indicate the prognostic significance of circulating omentin levels in HGSC patients.

We then soughtto delineate the mechanism by which omental adipose tissue interact with ovarian cancer cells to promote tumor growth and progression. We demonstrated previously using a co-culture model that omentin-induced glucose uptake in adipocytes may deplete the surrounding glucose that fuels the glucose-addicted ovarian cancer cells in the omental microenvironment and thus drive metabolic shift in ovarian cancer cells. We further studied the effect of omentin on the metabolic reprograming of ovarian cancer cells in vivo, and performed MALDI-imaging mass spectrometry on omental tumor tissue sections collected from mice treated with omentin. The results showed that tumor cells had markedly reduced hexose-6-phosphate (glucose-6-phosphate and fructose-6-phosphate) levels, and adipocytes adjacent to the tumor cells had increased hexose-6-phosphate levels. These findings suggested that omentin treatment induced a local rapid metabolic coupling between adipocytes and the neighboring metastatic ovarian cancer cells.

In conclusion, we show that adipocytes play an important role in putting competitive nutritional pressure on ovarian cancer cells by depleting glucose through omentin-stimulated uptake. The competitive uptake of glucose by adipocytes leads to glucose starvation of the malignant cells. Further studies to develop omentin as a therapeutic for HGSC to improve patients’ survival rates are warranted.