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Published on: July 17, 2019
RSK2 inactivation cooperates with AXIN1 inactivation or β-catenin activation to promote hepatocarcinogenesis
Samantha Schaeffer1, Barkha Gupta1, Anna-Line Calatayud1
1Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France; Functional Genomics of Solid Tumors Laboratory, équipe Labellisée Ligue Nationale Contre le Cancer, Paris, France.
Background & Aims:
Recurrent somatic mutations of the RPS6KA3 gene encoding for the serine/threonine kinase RSK2 were identified in hepatocellular carcinomas (HCCs), suggesting its tumour-suppressive function. Our goal was to demonstrate the tumour suppressor role of RSK2 in the liver and investigate the functional consequences of its inactivation.
Methods:
We analysed a series of 1,151 human HCCs for RSK2 mutations and 20 other driver genetic alterations. We then modelled RSK2 inactivation in mice in various mutational contexts recapitulating or not those naturally found in human HCC, using transgenic mice and liver-specific carcinogens. These models were monitored for liver tumour appearance and subjected to phenotypic and transcriptomic analyses. Functional consequences of RSK2 rescue were also investigated in a human RSK2-deficient HCC cell line.
Results:
RSK2-inactivating mutations are specific to human HCC and frequently co-occur with AXIN1-inactivating or β-catenin-activating mutations. Modelling of these co-occurrences in mice showed a cooperative effect in promoting liver tumours with transcriptomic profiles recapitulating those of human HCCs. By contrast, there was no cooperation in liver tumour induction between RSK2 loss and BRAF-activating mutations chemically induced by diethylnitrosamine. In human liver cancer cells, we also showed that RSK2 inactivation confers some dependency to the activation of RAS/MAPK signalling that can be targeted by MEK inhibitors.
Conclusions:
Our study demonstrates the tumour suppressor role of RSK2 and its specific synergistic effect in hepatocarcinogenesis when its loss of function is specifically combined with AXIN1 inactivation or β-catenin activation. Furthermore, we identified the RAS/MAPK pathway as a potential therapeutic target for RSK2-inactivated liver tumours.
Impact And Implications:
This study demonstrated the tumour suppressor role of RSK2 in the liver and showed that its inactivation specifically synergises with AXIN1 inactivation or β-catenin activation to promote the development of HCC with similar transcriptomic profiles as found in humans. Furthermore, this study highlights that activation of the RAS/MAPK pathway is one of the key signalling pathways mediating the oncogenic effect of RSK2 inactivation that can be targeted with already available anti-MEK therapies.
Insights
The serine/threonine kinase RSK2 acts as a tumour suppressor in liver cancer. Its inactivation synergizes with AXIN1 or beta-catenin mutations to promote hepatocellular carcinoma (HCC) development, suggesting RAS/MAPK pathway targeting for therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Recurrent mutations in RPS6KA3 (encoding RSK2) suggest a tumor suppressor role in hepatocellular carcinoma (HCC).
- Investigating RSK2's tumor suppressor function in the liver and the consequences of its inactivation is crucial for understanding HCC pathogenesis.
Purpose of the Study:
- To demonstrate the tumor suppressor role of RSK2 in liver cancer.
- To investigate the functional consequences of RSK2 inactivation in hepatocarcinogenesis.
Main Methods:
- Analysis of RSK2 mutations in 1,151 human HCCs and other driver mutations.
- Modeling RSK2 inactivation in mice in various genetic contexts using transgenic models and carcinogens.
- Phenotypic, transcriptomic, and functional rescue analyses in cell lines.
Main Results:
- RSK2 inactivating mutations are specific to human HCC and co-occur with AXIN1 or beta-catenin mutations.
- RSK2 loss cooperates with AXIN1/beta-catenin mutations to promote liver tumors with human HCC-like transcriptomes, but not with BRAF mutations.
- RSK2 inactivation in human HCC cells confers dependency on RAS/MAPK signaling, targetable by MEK inhibitors.
Conclusions:
- RSK2 functions as a tumor suppressor in the liver, synergizing with AXIN1 inactivation or beta-catenin activation in hepatocarcinogenesis.
- RAS/MAPK pathway activation is a key mediator of oncogenesis upon RSK2 inactivation, presenting a therapeutic target for RSK2-deficient HCC.
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