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bioRxiv · 10.1101/541326

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness.

Gargini, R.·Segura-Collar, B.·Hernandez-SanMiguel, E.·Garcia-Escudero, V.·Romero-Bravo, A.·Herranz, B.·Nunez, F. J.·Garcia-Perez, D.·Ayuso-Sacido, A.·Seoane, J.·Sepulveda-Sanchez, J. M.·Hernandez-Lain, A.·Castro, M. G.·Garcia-Escudero, R.·Avila, J.·Sanchez-Gomez, P.
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Abstract

Classification of gliomas as wild-type or mutant IDH1/2 tumors has profound clinical implications. However, how these two groups of gliomas progress, in a microenvironment-dependent manner, is still a pending question. Here we describe that the expression of Tau is epigenetically induced by mutant IDH1/2, whereas is almost absent from tumors with EGFR/PTEN mutations. Moreover, Tau (MAPT) expression is inversely correlated with overall survival in EGFR-amplified gliomas. Using orthotopic EGFR-related models, we have observed that Tau overexpression or microtubule stabilizers impair the mesenchymal transformation of glioma cells, with profound changes in tumor vasculature and a significant decrease in tumor burden. However, epithelial-to-mesenchymal transformed EGFR-mutant cells, acting as pericytes, induce neo-vasculogenesis and favor aggressive glioma growth, a process that is no longer sensitive to Tau. Altogether our data indicate that the genomic background controls glioma aggressiveness by modifying the vascular microenvironment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/541326v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1c4b33forg.highwire.dtl.DTLVardef@d3f636org.highwire.dtl.DTLVardef@1c957c1org.highwire.dtl.DTLVardef@1a04a0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Gargini, R., Segura-Collar, B., Hernandez-SanMiguel, E., Garcia-Escudero, V., Romero-Bravo, A., Herranz, B., Nunez, F. J., Garcia-Perez, D., Ayuso-Sacido, A., Seoane, J., Sepulveda-Sanchez, J. M., Hernandez-Lain, A., Castro, M. G., Garcia-Escudero, R., Avila, J., Sanchez-Gomez, P.. 2019-02-07. The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness.. https://doi.org/10.1101/541326

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