Emerging role of oncogenic β-catenin in exosome biogenesis as a driver of immune escape in hepatocellular carcinoma
Curation statements for this article:-
Curated by eLife
eLife assessment:
This study reports compelling data supporting the role of beta-catenin on intercellular communication occurring via extracellular vesicles, with implications for immune evasion in hepatocellular carcinoma (HCC). This fundamental insight sheds light on the underlying biology of HCC at a time when an increasing number of treatment options, including targeted small molecular inhibitors and immuno-oncologic drugs are being used to treat patients in the absence of validated predictive biomarkers. This work will be of special interest to researchers investigating the basic biology of liver function and HCC, and also to readers investigating novel pathways for therapeutic targeting of HCC.
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- Cancer Biology (eLife)
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 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 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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eLife assessment:
This study reports compelling data supporting the role of beta-catenin on intercellular communication occurring via extracellular vesicles, with implications for immune evasion in hepatocellular carcinoma (HCC). This fundamental insight sheds light on the underlying biology of HCC at a time when an increasing number of treatment options, including targeted small molecular inhibitors and immuno-oncologic drugs are being used to treat patients in the absence of validated predictive biomarkers. This work will be of special interest to researchers investigating the basic biology of liver function and HCC, and also to readers investigating novel pathways for therapeutic targeting of HCC.
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Reviewer #1 (Public Review):
Summary:
This finding shows a connection between cancer-associated beta-catenin mutations and extracellular vesicle secretion. A link between the beta-catenin mutation and expression of trafficking and exocytosis machinery. They used a multidisciplinary approach to explore expression levels of relevant proteins and single-particle imaging to directly explore the release of extracellular vesicles. These results suggest a role of extracellular vesicles in immune evasion in liver cancer with the role needing to be further explored in other forms of cancer. I find this work to be compelling and of strong significance.
Strengths:
This paper uses multidisciplinary methods to demonstrate the compelling role of beta-catenin mutations in suppressing EV secretion in tumors. The results and imaging are extremely …
Reviewer #1 (Public Review):
Summary:
This finding shows a connection between cancer-associated beta-catenin mutations and extracellular vesicle secretion. A link between the beta-catenin mutation and expression of trafficking and exocytosis machinery. They used a multidisciplinary approach to explore expression levels of relevant proteins and single-particle imaging to directly explore the release of extracellular vesicles. These results suggest a role of extracellular vesicles in immune evasion in liver cancer with the role needing to be further explored in other forms of cancer. I find this work to be compelling and of strong significance.
Strengths:
This paper uses multidisciplinary methods to demonstrate the compelling role of beta-catenin mutations in suppressing EV secretion in tumors. The results and imaging are extremely convincing and compelling.
Weaknesses:
There is no major weakness in this work. There are only things that left me more intrigued about this work. While the role of Rab27 was strongly examined, the hits of the VAMP proteins were not explored in detail. I was wondering if the decrease in the presence of VAMPS directly suggests the final step of membrane fusion in the exocytosis of EVs is what is being impaired. Or if it is other trafficking steps along the EV secretion pathway.
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Reviewer #2 (Public Review):
Summary:
Dantzer and colleagues are investigating the pivotal role of ß-catenin, a gene that undergoes mutation in various cancer cells, and its influence on promoting the evasion of immune cells. In their initial experiments, the authors developed a HepG2 mutated ß-catenin KD model, conducting transcriptional and proteomic analyses. The results revealed that the silencing of mutated ß-catenin in HepG2 cells led to an up-regulation in the expression of exosome biogenesis genes.
Furthermore, the researchers verified that these KD cells exhibited increased production of exosomes, with the mutant form of ß-catenin concurrently decreasing the expression of SDC4 and Rab27a. Intriguingly, applying a GSK inhibitor to the cells resulted in reduced expression of SDC4 and Rab27a. Subsequent findings indicated that …
Reviewer #2 (Public Review):
Summary:
Dantzer and colleagues are investigating the pivotal role of ß-catenin, a gene that undergoes mutation in various cancer cells, and its influence on promoting the evasion of immune cells. In their initial experiments, the authors developed a HepG2 mutated ß-catenin KD model, conducting transcriptional and proteomic analyses. The results revealed that the silencing of mutated ß-catenin in HepG2 cells led to an up-regulation in the expression of exosome biogenesis genes.
Furthermore, the researchers verified that these KD cells exhibited increased production of exosomes, with the mutant form of ß-catenin concurrently decreasing the expression of SDC4 and Rab27a. Intriguingly, applying a GSK inhibitor to the cells resulted in reduced expression of SDC4 and Rab27a. Subsequent findings indicated that mutated ß-catenin actively facilitates immune escape through exosomes, and silencing exosome biogenesis correlates with a decrease in immune cell infiltration.
In a crucial clinical correlation, the study demonstrated that patients with ß-catenin mutations exhibited low levels of exosome biogenesis.Strengths:
Overall, the data robustly supports the outlined conclusions, and the study is commendably designed and executed. However, there are a few suggestions for manuscript improvement.
Weaknesses:
No weaknesses were identified by this reviewer. -
Reviewer #3 (Public Review):
Summary:
In this very important study by Dantzer et al., 'Emerging role of oncogenic b-catenin in exosome biogenesis as a driver of immune escape in hepatocellular carcinoma' the authors define a role for oncogenic b-catenin on exosome biology and explore the link between reduce exosome secretion and tumor immune cell evasion. Using transcriptional and proteomic analysis of hepatocellular carcinoma cells with either oncogenic or wildtype b-catenin the authors find that oncogenic b-catenin negatively regulates exosome biogenesis.
The authors can provide compelling evidence that oncogenic b-catenin in different hepatocellular carcinoma cells negatively regulates exosome biogenesis and secretion, by downregulation of, amongst others, SDC4 and RAB27A, two proteins involved in exosome biogenesis. The authors …
Reviewer #3 (Public Review):
Summary:
In this very important study by Dantzer et al., 'Emerging role of oncogenic b-catenin in exosome biogenesis as a driver of immune escape in hepatocellular carcinoma' the authors define a role for oncogenic b-catenin on exosome biology and explore the link between reduce exosome secretion and tumor immune cell evasion. Using transcriptional and proteomic analysis of hepatocellular carcinoma cells with either oncogenic or wildtype b-catenin the authors find that oncogenic b-catenin negatively regulates exosome biogenesis.
The authors can provide compelling evidence that oncogenic b-catenin in different hepatocellular carcinoma cells negatively regulates exosome biogenesis and secretion, by downregulation of, amongst others, SDC4 and RAB27A, two proteins involved in exosome biogenesis. The authors corroborate these results by inducing b-catenin activation using CHIR99021 in a hepatocarcinoma cell line with non-oncogenic bCatenin (Huh7 cells). The authors can further demonstrate convincingly that a reduction in exosome release by hepatocarcinoma spheroids leads to a reduction in immune cell infiltration into the tumor spheroid.
Strengths:
This is a very important and well-conceived study, that appeals to a readership beyond the field of hepatocarcinoma. The authors demonstrate a compelling link between oncogenic bCatenin and exosome biogenesis. Their results are convincing and with well-designed control experiments. The authors included various complementary lines of investigation to verify their findings.
Weaknesses:
One limitation of this study is that the mechanistic relationship of exosome release and how they affect immune cells remains to be elucidated. In this context, the authors conclusions rest on the assumption that hepatocarcinoma immune evasion is based exclusively on the reduced number of exosomes. However, the authors do not analyze exosome composition between exosomes of wild type and oncogenic background, which could be different.
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