Emerging role of oncogenic ß-catenin in exosome biogenesis as a driver of immune escape in hepatocellular carcinoma

• DOI: 10.7554/elife.95191.3
• Publication Date: 2024-07-15T16:50:44Z
• Authors: Camille Dantzer; Justine Vaché; Aude Brunel; Isabelle Mahouche; Anne-Aurélie Raymond; Jean-William Dupuy; Melina Petrel; Paulette Bioulac-...; David Perrais; Nathalie Dugot-Se...; Mireille Verdier; Barbara Bessette; Clotilde Billottet; Violaine Moreau
• Keywords: Carcinoma, Hepatocellular; QH301-705.5; Science; 610; [SDV.CAN]Life Sciences [q-bio]/Cancer; [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry; exosomes; ß-catenin; liver; Exosomes; rab27 GTP-Binding Proteins; Cell Line, Tumor; Tumor Microenvironment; cancer; Humans; Biology (General); beta Catenin; Cancer Biology; Molecular Biology/Genomics [q-bio.GN]; Q; Liver Neoplasms; R; [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology; Gene Expression Regulation, Neoplastic; [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology; Mutation; Medicine; Tumor Escape; extracellular vesicles

Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of ß-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic ß-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of ß-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated ß-catenin represses expression of SDC4 and RAB27A, two main actors in exosome biogenesis, in both liver cancer cell lines and HCC patient samples. Using nanoparticle tracking analysis and live-cell imaging, we further demonstrated that activated ß-catenin represses exosome release. Then, we demonstrated in 3D spheroid models that activation of β-catenin promotes a decrease in immune cell infiltration through a defect in exosome secretion. Taken together, our results provide the first evidence that oncogenic ß-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of ß-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response.