Altered fatty acid metabolism rewires cholangiocarcinoma stemness features.

Autor: Lori, G., Pastore, M., Navari, N., Piombanti, B., Booijink, R., Rovida, E., Tusa, I., Lewinska, M., Andersen, J.B., Lottini, T., Arcangeli, A., Taddei, M.L., Pranzini, E., Madiai, S., Sacco, E., Rota, S., Trapani, A., Agrimi, G., Ramazzotti, M., Ostano, P.
Zdroj: Digestive & Liver Disease; Sep2023:Supplement 3, Vol. 55, pS225-S226, 2p
Abstrakt: Metabolic reprogramming of cancer stem cells (CSC) has been intensively investigated in recent years. Nevertheless, the role of lipids in the control of tumor-stemness in intrahepatic cholangiocarcinoma (iCCA) remains to be elucidated. Our study aimed to explore the contribution of fatty acids (FA) in the regulation of stem-like features in iCCA. iCCA cells grown as 3D spheres (SPH) were used to enrich for stem-like cells. Parental cells grown as monolayer (MON) were used as control. Triglyceride (TG) composition and de novo synthesis products were quantified by LC-MS/QTOF and used for desaturation index calculation. NOD/SCID mice were injected with iCCA-SPH cells and treated with the fatty acid synthase (FASN) inhibitor orlistat. Five-year overall survival was analyzed in 68 patients with iCCA, sub-grouped based on FASN expression. In vitro exposure of iCCA-MON cells to oleic or palmitoleic monounsaturated FA (MUFA) enhanced stem-like features at both functional (resistance to antineoplastic drugs, spherogenicity) and molecular level (expression of stemness associated genes). Metabolically, iCCA-SPH retained superior unsaturated TG-content in accordance with upregulation of several genes involved in FA metabolism compared to MON. In patients with iCCA, tissue expression levels of FASN, a key gene involved in FA synthesis, correlated with overall survival. In vitro FASN inhibition by orlistat or its depletion by siRNA decreased sphere-forming ability and expression of stem-like markers. In a murine xenograft model obtained by injection of iCCA-SPH, orlistat significantly inhibited tumor growth and resulted in both downregulation of proliferative markers and upregulation of tumor suppressor genes. These data provide evidence that an altered FA metabolism contributes to the maintenance of stem-like phenotype in iCCA. Moreover, FASN might be of relevance for CSC-promoting function in iCCA. [ABSTRACT FROM AUTHOR]
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