IDH-Tau-EGFR triad defines the neovascular landscape of diffuse gliomas by controlling mesenchymal differentiation
Science Translational Medicine(2019)
Abstract
Mutant IDH1/2 gliomas represent a more indolent form of cancer. However, how this group of tumors evolve, 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, the level of Tau decreases when the tumor progresses. Besides, 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. Here, we demonstrate that the overexpression of Tau, through the stabilization of microtubules, impairs the mesenchymal/pericyte-like transformation of glioma cells by blocking 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 and rendering the tumors more sensitive to chemotherapy.
One Sentence Summary Tau, which is induced by IDH mutations, inhibits the EGFR/NF-kB/TAZ axis and impairs the mesenchymal/pericyte-like transformation of glioma cells, normalizing the vasculature and impairing tumor aggressiveness.
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