Concurrence of FGFR1 mutations modulates oncogenesis in glioneuronal tumors
FGFR1 genetic alterations are associated with brain malignancies, including FGFR1 mutations in familial and sporadic cases of low-grade glioneuronal tumors, suggesting intrinsic mechanisms of selective pressure toward FGFR1 multiple events arising in the context of a quiet genome. To decipher the mo...
| Autores: | , , , , , , , , , , , , , , , , , , |
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| Formato: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Recursos: | Universitat Ramon Llull (URL) |
| Repositorio: | DAU Arxiu Digital de la Universitat Ramon Llull |
| OAI Identifier: | oai:dau.url.edu:20.500.14342/5771 |
| Acesso em linha: | http://hdl.handle.net/20.500.14342/5771 https://doi.org/10.1038/s44318-025-00600-3 |
| Access Level: | acceso abierto |
| Palavra-chave: | FGFR1 Multiple Mutations Glioneuronal Tumors Cell Models Modulatory Mechanisms Mutació (Biologia) Sistema nerviós--Tumors 616 616.8 |
| Resumo: | FGFR1 genetic alterations are associated with brain malignancies, including FGFR1 mutations in familial and sporadic cases of low-grade glioneuronal tumors, suggesting intrinsic mechanisms of selective pressure toward FGFR1 multiple events arising in the context of a quiet genome. To decipher the molecular mechanisms triggered by multiple concurrent FGFR1 mutations, we have mapped the proximal interactome of wild-type, single- and double-mutant FGFR1 proteins through a BioID-MS approach. Our data reveal novel oncogenic functionality for the two hotspot mutations N546K and K656E, linked to evasion of lysosomal degradation. Further, we identified a modulatory tumor-suppressive role for the susceptibility variant R661P, which hampers the oncogenic potential of both hotspot N546K and K656E mutations by rescuing receptor degradation and reducing N546K affinity for the downstream effector PLCγ. Introducing the R661P missense variant was sufficient to abolish self-renewal capacity of oligodendroglioma cells and downregulate genes involved in neurodevelopment and neuro-glial cell fate decisions, both aspects overcome in the double mutants. This study sheds light on contextual oncogenic effects associated with FGFR1 alterations and their recurrence in low-mutation burden and therapy naive tumors. |
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