Medulloblastoma, the most common malignant brain tumor of childhood, exhibits significant biological complexity that demands deeper exploration. Here, we present a large multiomics dataset integrating data from 384 primary medulloblastoma patient samples across five omic layers: CpG methylome, transcriptome, proteome, phosphoproteome, and metabolome, paired with associated clinical metadata. Data integration revealed intertumoral heterogeneity of lipid metabolism across proteomic subtypes. Notably, while the MYC-FASN-SCD axis drives lipid biosynthesis, pathway inhibition elicits a compensatory escape mechanism in vivo through exogenous fatty acid uptake. Unexpectedly, we demonstrated that MYC triggers lipid storage, creating a unique dependency on lipid droplet-mitochondria communications to sustain tumor maintenance in vivo. Together, this comprehensive analysis reveals a targetable vulnerability downstream of MYC that constitutes a promising therapeutic approach to treat currently untreatable medulloblastoma subtypes.
Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma / Bernardi, F.; Torrejon, J.; Basili, I.; Van Ommeren, R.; Marsaud, V.; Yu, H.; Talbot, J.; Souphron, J.; Indersie, E.; Forget, A.; Bonneau, B.; Massiot, A.; Alcazar, C.; Figeac, L.; Bonerandi, E.; Cancila, G.; Sirbu, O.; Yadav, N.; Mohanakrishnan, D.; Lombard, B.; Loew, D.; Poullet, P.; Liva, S.; Lovino, M.; Lin, I. H.; Nakashima, T.; Gharsalli, T.; Nicolas, P. A.; Yubuki, N.; Ribas, R. A.; Colsch, B.; Chu-Van, E.; Castelli, F.; Sampaio, J. L.; Leboucher, S.; Lasgi, C.; Besse, L.; Soler, M. N.; Lo Re, V.; Planque, N.; Abeysundara, N.; Balin, P.; Wang, H.; Su, H.; Wu, X.; Cavalli, F. M. G.; Saulnier, O.; Ficarra, E.; Di Marcotullio, L.; Kumegawa, K.; Maruyama, R.; Kawauchi, D.; Picard, D.; Remke, M.; Riffaud, L.; Puiseux, C.; Bouchoucha, Y.; Huybrechts, S.; Simbozel, M.; Bourdeaut, F.; Varlet, P.; Puget, S.; Blauwblomme, T.; Andrianteranagna, M.; Planchon, J. M.; Dugourd, A.; Saez-Rodriguez, J.; Barillot, E.; Servant, N.; Martignetti, L.; Rich, J.; Kool, M.; Pfister, S. M.; Agnihotri, S.; Suzuki, H.; Fanjul, M.; Wang, W. J.; Tsai, J. W.; Sun, R. C.; Beccaria, K.; Dufour, C.; Sarry, J. E.; Michealraj, K. A.; Taylor, M. D.; Ayrault, O.. - In: CANCER CELL. - ISSN 1535-6108. - 44:2(2026), pp. 383-404.e18. [10.1016/j.ccell.2025.12.012]
Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma
Lovino M.;Ficarra E.;Martignetti L.;
2026
Abstract
Medulloblastoma, the most common malignant brain tumor of childhood, exhibits significant biological complexity that demands deeper exploration. Here, we present a large multiomics dataset integrating data from 384 primary medulloblastoma patient samples across five omic layers: CpG methylome, transcriptome, proteome, phosphoproteome, and metabolome, paired with associated clinical metadata. Data integration revealed intertumoral heterogeneity of lipid metabolism across proteomic subtypes. Notably, while the MYC-FASN-SCD axis drives lipid biosynthesis, pathway inhibition elicits a compensatory escape mechanism in vivo through exogenous fatty acid uptake. Unexpectedly, we demonstrated that MYC triggers lipid storage, creating a unique dependency on lipid droplet-mitochondria communications to sustain tumor maintenance in vivo. Together, this comprehensive analysis reveals a targetable vulnerability downstream of MYC that constitutes a promising therapeutic approach to treat currently untreatable medulloblastoma subtypes.
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