The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas

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 (MAPT), 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, MAPT was almost absent from tumors with epidermal growth factor receptor (EGFR) mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) EGFR. 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.This work was supported by NIH/ NINDS grants R01-NS105556 and R37-ND094804 to M.G.C.; by Ministerio de Economía y Competitividad (Acción Estratégica en Salud) grants PI13/01258 to A.H.-L., PI17/01489 and CP11/00147 to A.A.-S., PI18/00263 to R.G.-E., and PI16/01 278 to J.S.; by “Asociación Española contra el Cancer” grants Investigador Junior to R.G. and GCTRA16015SEDA to J.M.S.-S. and J.S.; and by Ministerio de Economía y Competitividad SAF-2014-53040-P to J.A., RTC-2015-3771-1 to J.S., and SAF2015-65175-R/FEDER to P.S.-GPeer reviewe