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oai:repisalud.isciii.es:20.500.12105/271592026-01-20T01:21:07Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617

00925njm 22002777a 4500 dc Gargini, Ricardo author Sánchez-Gómez, Pilar author Segura-Collar, Berta author Herránz, Beatriz author García-Escudero, Vega author Romero-Bravo, Andrés author Núñez, Felipe J author García-Pérez, Daniel author Gutiérrez-Guamán, Jacqueline author Ayuso-Sacido, Angel author Seoane, Joan author Pérez-Núñez, Angel author Sepúlveda-Sánchez, Juan M author Hernández-Laín, Aurelio author Castro, María G author García-Escudero, Ramón author Ávila, Jesús author Sánchez-Gómez, Pilar author 2020-01-22 Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, was almost absent from tumors with epidermal growth factor receptor () mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy. Gargini R, Segura-Collar B, Herránz B, García-Escudero V, Romero-Bravo A, Núñez FJ, García-Pérez D, Gutiérrez-Guamán J, Ayuso-Sacido A, Seoane J, Pérez-Núñez A, Sepúlveda-Sánchez JM, Hernández-Laín A, Castro MG, García-Escudero R, Ávila J, Sánchez-Gómez P. The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas. Sci Transl Med. 2020 Jan 22;12(527):eaax1501. doi: 10.1126/scitranslmed.aax1501. PMID: 31969485; PMCID: PMC7055928. 10.1126/scitranslmed.aax1501 Science Translational Medicine 31969485 https://hdl.handle.net/20.500.12105/27159 The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas.