Role of SMARCB1 in the metabolic perturbations associated with the malignant transformation in Rhabdoïd Tumors
Laury Poulain1, Julien Masliah-Planchon1, Marie-Ming Aynaud1, Mamy Andrianteranagna1, Sylvere Durand2, Guido Kroemer3 and Olivier Delattre1 1Institut Curie, INSERM U830 & SIREDO, Institut Curie, Paris, France ; 2Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, Villejuif, France; 3CRC, INSERM U 1138, Paris, France
Malignant Rhabdoid Tumors (MRT) are rare aggressive tumors frequently observed in young children. They are characterized by bi-allelic inactivating mutations of SMARCB1 in almost 95% of cases. As metabolic reprogramming is a common phenotype observed in cancer cells, principally to support rapid proliferation, we investigated metabolic changes associated with the loss-of-function of SMARCB1.
Using a tetracycline based SMARCB1-inducible system in a SMARCB1-deficient malignant rhabdoid tumor cell line (I2A) we performed RNAseq analysis and we observed that the expression of the genes encoding enzymes of the SSP pathway is increased. Especially PHGDH which is the rate-limiting enzyme in this metabolic pathway transforming 3-phosphoglycerate into 3-phosphohydroxypyruvate. Metabolomic and tracking analyses (U-[13C]-glucose and U-[13C]-serine) confirm that the SSP is deregulated in SMARCB1 deficient cells and further show that serine is directly supplied by the glycolysis. This leads to increased serine production, fueling the one carbon metabolism (OCM). In contrast this pathway is poorly active in rhabdoid cells which re-express SMARCB1. We also showed with RNAseq data that the transsulfuration pathway genes, involved in OCM (CTH, CBS) are upregulated in rhabdoid cell lines. Metabolomics and tracking analysis show an increased production of reduced glutathione (GSH) and a decreased production of oxidized glutathione (GSSG) in rhabdoid cells which may constitute a protection against oxidative stress. In contrast, re-expression of SMARCB1 decreases production of GSH and increases cytoplasmic ROS production observed by FACS analysis.
Our results strongly suggest that targeting SSP in MRT seems to be a promising therapeutic strategy.