Deciphering tumor acidosis and its role in chemotherapy tolerance : insights for therapeutic exploitation
(2025)
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- Authors
- Supervisors
- Feron, Olivier
- Abstract
- The acidic tumor microenvironment is driven by high metabolic activity and reduced proton clearance. Acidosis prompts cancer cells to rely less on glucose and more on fatty acid metabolism for survival. This metabolic shift presents a potential vulnerability that can be targeted with metabolic inhibitors. We identified the desaturase SCD1 as crucial for the survival of acidic cancer cells characterized by carbonic anhydrase 9 (CA9) expression and moderate oxygenation. Inhibiting SCD1 disrupts lipid droplet formation, making acidic cells more susceptible to peroxidation of polyunsaturated fatty acids, and associated ferroptosis. This process also triggers a bystander effect, leading to endoplasmic reticulum stress in hypoxic cells. In parallel, we found that CA9+ cells in 3D tumor spheroids resist chemotherapy by accumulating cholesterol esters. Statins, which inhibit cholesterol synthesis, prevent tumor regrowth after chemotherapy, supporting a role of cholesterol in drug tolerance.
- Affiliations
Citations
Glowacka, K. (2025). Deciphering tumor acidosis and its role in chemotherapy tolerance : insights for therapeutic exploitation. https://hdl.handle.net/2078.5/242376