Cholangiocarcinoma cells direct fatty acids to support membrane synthesis and modulate macrophage phenotype

作者：Michele Dei, Stefania Mantovani, Barbara Oliviero, Aı́da Zulueta, Linda Montavoci, Monica Falleni, Delfina Tosi, Camillo Morano, Sara Penati, Annalisa Chiocchetti, Riccardo Sinella, Camilla Barbero Mazzucca, Matteo Donadon, Cristiana Soldani, Gaetano Piccolo, Matteo Barabino, Paolo Pietro Bianchi, Marcello Maestri, Ana Lleò, Jesús M. Bañales, Mario U. Mondelli, Anna Caretti · 发表于：Hepatology Communications · 年份：2025 · DOI：10.1097/hc9.0000000000000717 · 被引用次数：3 · 研究领域：Cancer, Lipids, and Metabolism、Caveolin-1 and cellular processes、Lipid metabolism and biosynthesis

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a globally rare, increasingly incident cancer. Metabolic reprogramming is common in cancer cells, and altered lipid homeostasis favors tumor development and progression. Previous studies have described lipid deregulation in HCC cells, while in CCA, the lipidome profile is still poorly characterized. METHODS: We used liquid chromatography-tandem mass spectrometry to examine the lipid level profile of intrahepatic CCA (iCCA) and non-tumor surrounding tissue from patients, as well as in patients' and healthy controls' sera. RESULTS: All lipid classes were upregulated in tumor specimens and iCCA-derived sera. Newly synthesized fatty acids (FAs) accumulated in iCCA and were only marginally directed to mitochondrial β-oxidation and scarcely folded in lipid droplets as neutral species. Metabolic flux assay showed that FAs were instead redirected toward plasma membrane formation and remodeling, being incorporated into phospholipids and sphingomyelin. A distinct lipid droplet and macrophage distribution was revealed by immunohistochemistry and Imaging Mass Cytometry. Lipid droplets were fewer in iCCA than in normal tissue and present mainly in the intratumoral fibrous septa and in M2 macrophages. Monocytes modified their lipid content and phenotype in the presence of iCCA cells, and the same effect could be recapitulated by FA supplementation. CONCLUSIONS: Our results reveal a profound alteration in the lipid content of iCCA tissues and...