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

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.

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature

“…4B and Supplementary Fig. 5), suggesting a direct correlation between the absence of IDH mutations and the increase in tumor pericytes, as we have recently described 11 .…”

“…5A-B). This result was not surprising given that the MAPT/Tau gene is epigenetically induced by the presence of mutant IDH proteins 11 . However, we also found an enrichment of Tau in GBMwt_lo compared to GBMwt_hi tumors ( Fig.…”

“…These effects were associated with a limited capacity of the gliomas cells to contribute to the pool of pericytes in Tau-high tumors, which results in a reduced amount of dilated BVs and a less efficient fueling of tumor growth 11 . We measured the amount of Tau in our cohort of gliomas and we observed that it accumulates in IDHmut gliomas (Fig.…”

“…We have previously shown that the Tau expression is induced by IDH mutations and repressed by wild-type IDH1 11 , which is upregulated in primary GBs and promotes aggressive growth and therapy resistance 18 . Moreover, it has been shown that the expression of wild-type IDH1…”

“…Notably, we have observed a direct correlation between the immune content and the presence of vascular alterations, as well as with the reduced expression of Tau. We have recently described that this microtubule-bindingprotein impairs the neovascularization of gliomas 11 . Here, we have shown that overexpression of Tau reduces the immune content in orthotopic glioma models, delaying tumor growth.…”