Emerging role of oncogenic β-catenin in exosome biogenesis as a driver of immune escape in hepatocellular carcinoma
ABSTRACT Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of β-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic β-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of β-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated β-catenin represses expression ofSDC4andRAB27A, 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 β-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 β-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of β-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 03. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dantzer, Camille [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.10.24.563805 |
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| PPN (Katalog-ID): |
XBI041339827 |
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| 520 | |a ABSTRACT Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of β-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic β-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of β-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated β-catenin represses expression ofSDC4andRAB27A, 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 β-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 β-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of β-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response. | ||
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