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

Ricardo Gargini, Berta Segura-Collar, Esther Hernandez-SanMiguel, Vega Garcia-Escudero, Andres Romero-Bravo, Beatriz Herranz, Felipe J Nunez, Daniel Garcia-Perez, Angel Ayuso-Sacido, Joan Seoane, Juan Manuel Sepulveda-Sanchez, Aurelio Hernandez-Lain, Maria G Castro, Ramon Garcia-Escudero, Jesus Avila, Pilar Sanchez-Gomez
doi: https://doi.org/10.1101/541326
Ricardo Gargini
Centro de Biologia Molecular (CSIC-UAM), Madrid, Spain;
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Berta Segura-Collar
Instituto de Salud Carlos III-UFIEC, Madrid, Spain;
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Esther Hernandez-SanMiguel
Instituto de Salud Carlos III-UFIEC, Madrid, Spain;
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Vega Garcia-Escudero
Facultad de Medicina de la Universidad Autonoma, Madrid, Spain;
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Andres Romero-Bravo
Instituto de Salud Carlos III-UFIEC, Madrid, Spain;
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Beatriz Herranz
Facultad de Medicina de la Universidad Francisco de Vitoria, Madrid, Spain;
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Felipe J Nunez
The University of Michigan School of Medicine, Ann Arbor, MI, USA.;
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Daniel Garcia-Perez
Hospital 12 de Octubre, Madrid, Spain;
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Angel Ayuso-Sacido
HM Hospitales, Madrid, Spain;
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Joan Seoane
Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain;
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Juan Manuel Sepulveda-Sanchez
Hospital 12 Octubre, Madrid, Spain;
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Aurelio Hernandez-Lain
Hospital 12 de Octubre;
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Maria G Castro
The University of Michigan School of Medicine, Ann Arbor, MI, USA;
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Ramon Garcia-Escudero
CIEMAT, Madrid, Spain;
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Jesus Avila
Centro de Biologia Molecular (CSIC-UAM), Madrid, Spain;
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Pilar Sanchez-Gomez
Instituto De Salud Carlos III, Madrid, Spain
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  • For correspondence: psanchezg@isciii.es
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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.

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Posted February 07, 2019.
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The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness.
Ricardo Gargini, Berta Segura-Collar, Esther Hernandez-SanMiguel, Vega Garcia-Escudero, Andres Romero-Bravo, Beatriz Herranz, Felipe J Nunez, Daniel Garcia-Perez, Angel Ayuso-Sacido, Joan Seoane, Juan Manuel Sepulveda-Sanchez, Aurelio Hernandez-Lain, Maria G Castro, Ramon Garcia-Escudero, Jesus Avila, Pilar Sanchez-Gomez
bioRxiv 541326; doi: https://doi.org/10.1101/541326
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The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness.
Ricardo Gargini, Berta Segura-Collar, Esther Hernandez-SanMiguel, Vega Garcia-Escudero, Andres Romero-Bravo, Beatriz Herranz, Felipe J Nunez, Daniel Garcia-Perez, Angel Ayuso-Sacido, Joan Seoane, Juan Manuel Sepulveda-Sanchez, Aurelio Hernandez-Lain, Maria G Castro, Ramon Garcia-Escudero, Jesus Avila, Pilar Sanchez-Gomez
bioRxiv 541326; doi: https://doi.org/10.1101/541326

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