RSK2 inactivation cooperates with AXIN1 inactivation or ß-catenin activation to promote hepatocarcinogenesis - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Hepatology Année : 2023

RSK2 inactivation cooperates with AXIN1 inactivation or ß-catenin activation to promote hepatocarcinogenesis

Résumé

Background & Aims : Recurrent somatic mutations of RPS6KA3 gene encoding for the serine/threonine kinase RSK2 were identified in hepatocellular carcinomas (HCC) suggesting its tumor suppressive function. Our goal was to demonstrate the tumor suppressor role of RSK2 in the liver and investigate the functional consequences of its inactivation. Methods : We analyzed a series of 1151 human HCCs for RSK2 mutations and 20 other driver genetic alterations. We then modeled 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 tumor appearance and subjected to phenotypic and transcriptomic analyzes. Functional consequences of RSK2 rescue were also investigated in a human RSK2 deficient HCC cell line. Results : RSK2 inactivating mutations are specific of human HCC and frequently co-occur with AXIN1 inactivating or ß-catenin activating mutations. Modeling of these co-occurrences in mice showed cooperative effect in promoting liver tumors with transcriptomic profiles recapitulating those of human HCCs. By contrast, there was no cooperation in liver tumor 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 the RAS/MAPK signaling that can be targeted by MEK inhibitors. Conclusions : Our study newly demonstrated the tumor suppressor role of RSK2 and its specific synergistic effect in hepatocarcinogenesis when its loss of function is specifically combined with AXIN1 inactivation or ß-catenin activation. Furthermore, we identified the RAS/MAPK pathway as a potential therapeutic target for RSK2-inactivated liver tumors. Impact and implications : This study demonstrated the tumor suppressor role of RSK2 in the liver and showed that its inactivation specifically synergizes with AXIN1 inactivation or ß-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 signaling pathways mediating the oncogenic effect of RSK2 inactivation that can be targeted with already available anti-MEK therapies.
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Dates et versions

hal-04148084 , version 1 (02-07-2023)

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Samantha Schaeffer, Barkha Gupta, Anna-Line Calatayud, Julien Calderaro, Stefano Caruso, et al.. RSK2 inactivation cooperates with AXIN1 inactivation or ß-catenin activation to promote hepatocarcinogenesis. Journal of Hepatology, 2023, ⟨10.1016/j.jhep.2023.05.004⟩. ⟨hal-04148084⟩
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