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

• Published in: Science translational medicine 2020-01, Vol.12 (527)
• Main Authors: Gargini, Ricardo, Segura-Collar, Berta, Herránz, Beatriz, García-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
• Subjects: AMP; Angiogenesis; Animals; Blotting, Western; Brain tumors; Cell Line; Chemotherapy; Endothelial Cells - metabolism; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Glioma - genetics; Glioma - metabolism; Glioma cells; Humans; Immunohistochemistry; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Isoforms; Mesenchyme; Mice; Microtubule-associated proteins; Mutation - genetics; Neurodegenerative diseases; NF-κB protein; Reverse Transcriptase Polymerase Chain Reaction; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Transcription; Tumor cells
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aax1501

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.