Tau, downstream of IDH mut, inhibits the EGFR/NF-kB/TAZ mesenchymal axis, normalizing the vasculature and impairing glioma aggressiveness

• Published in: Science translational medicine 2020-01, Vol.12 (527)
• Main Authors: Gargini, Ricardo, Segura-Collar, Berta, Herránz, Beatriz, Garcia-Escudero, Vega, Romero-Bravo, Andrés, Núñez, Felipe J, García-Pérez, Daniel, Gutiérrez-Guamán, Jacqueline, Ayuso-Sacido, Angel, Seoane, Joan, Pérez-Núñez, Angel, Sepúlveda-Sánchez, Juan M., Hernández-Laín, Aurelio, Castro, María G., García-Escudero, Ramón, Ávila, Jesús, Sánchez-Gómez, Pilar
• Format: Article
• Language: English
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aax1501

Mutant IDH1/2 gliomas represent a more indolent form of cancer. However, how this group of tumors progress, in a microenvironment-dependent manner, is still a pending question. Here we describe that the expression of Tau, a gene classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wild-type and mutant IDH1/2 in gliomas. Moreover, Tau is almost absent from tumors with EGFR mutations, whereas its expression is inversely correlated with overall survival in gliomas carrying wild-type or amplified EGFR. We demonstrate that the overexpression of Tau, through the stabilization of microtubules, impairs the mesenchymal/pericyte transformation of EGFRamp/wt glioma cells through the blockade of the EGFR-NFκB-TAZ axis. However, mutant EGFR induces a constitutive activation of this pathway, which is no longer sensitive to Tau. By inhibiting the phenotypic plasticity of EGFRamp/wt glioma cells, Tau protein inhibits angiogenesis and favors vascular normalization, decreasing tumor aggressiveness.