Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal...

Area of Science:

• Oncology
• Cell Biology
• Metabolic Disease Therapeutics

Background:

• The tumor microenvironment (TME) is crucial for cancer progression, especially in ovarian cancer (OvCa) where the omentum is a primary site.
• Understanding the interactions within the omental TME is key to developing effective OvCa treatments.

Purpose of the Study:

• To investigate the effect of the diabetes drug metformin on the omental microenvironment in ovarian cancer.
• To elucidate the molecular mechanisms by which metformin disrupts tumor-stromal crosstalk in the omentum.

Main Methods:

• Analysis of mesothelial cells and ovarian cancer cells within an organotypic 3D model.
• Assessment of signaling pathways including TGF-β, CCL2, IL-8, and HIF1α.
• Measurement of tricarboxylic acid (TCA) enzyme SUCLG2 expression and succinate levels.

Main Results:

• Metformin blocks bidirectional signaling between OvCa cells and omental mesothelial cells.
• Metformin reduces mesothelial cell production of CCL2 and IL-8 by inhibiting SUCLG2 expression and succinate levels.
• Metformin leads to HIF1α degradation in mesothelial cells, disrupting IL-8 signaling and reducing OvCa invasion.

Conclusions:

• Metformin effectively targets tumor-promoting signaling within the omental TME of ovarian cancer.
• Inhibition of SUCLG2 and subsequent HIF1α degradation are key mechanisms for metformin's anti-cancer effects in this context.
• Metformin represents a potential therapeutic agent for targeting omental metastasis in ovarian cancer.