Research ArticleCancer

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

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Science Translational Medicine  22 Jan 2020:
Vol. 12, Issue 527, eaax1501
DOI: 10.1126/scitranslmed.aax1501

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The positive side of TAU

Gliomas, brain tumors originating in glial cells, are classified according to histologic as well as genetic features. Mutations in the IDH1/2 genes are associated with more favorable prognosis, whereas mutations in EGFR are characteristic of aggressive tumors. How these genes affect the microenvironment is not completely clear. Now, Gargini et al. show that TAU protein, classically associated with neurodegenerative disorders, is increased in less aggressive tumors. TAU inhibited the transition toward an aggressive phenotype by blocking EGFR activation. Mutated EGFR was no longer sensitive to TAU inhibition, possibly explaining the aggressive phenotype associated with EGFR mutations. The results suggest that TAU might play a main role in determining glioma aggressiveness.

Abstract

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.

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