eLife (Jul 2024)

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

  • Camille Dantzer,
  • Justine Vaché,
  • Aude Brunel,
  • Isabelle Mahouche,
  • Anne-Aurélie Raymond,
  • Jean-William Dupuy,
  • Melina Petrel,
  • Paulette Bioulac-Sage,
  • David Perrais,
  • Nathalie Dugot-Senant,
  • Mireille Verdier,
  • Barbara Bessette,
  • Clotilde Billottet,
  • Violaine Moreau

DOI
https://doi.org/10.7554/eLife.95191
Journal volume & issue
Vol. 13

Abstract

Read online

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.

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