1. Academic Validation
  2. Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas

Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas

  • Cancer Res. 2021 Apr 15;81(8):2142-2156. doi: 10.1158/0008-5472.CAN-20-3558.
Berta Segura-Collar 1 María Garranzo-Asensio 1 Beatriz Herranz 1 2 Esther Hernández-SanMiguel 1 Teresa Cejalvo 1 Bárbara S Casas 3 Ander Matheu 4 5 6 Ángel Pérez-Núñez 7 Juan Manuel Sepúlveda-Sánchez 8 Aurelio Hernández-Laín 8 Verónica Palma 3 Ricardo Gargini 9 Pilar Sánchez-Gómez 9
Affiliations

Affiliations

  • 1 Neurooncology Unit, Unidad Funcional de Investigación en Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
  • 2 Facultad de Medicina, Universidad Francisco de Vitoria, Madrid, Spain.
  • 3 Laboratory of Stem Cells and Developmental Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
  • 4 Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain.
  • 5 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
  • 6 CIBERFES, Instituto de Salud Carlos III, Madrid, Spain.
  • 7 Dto. Neurocirugía, Hospital 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain.
  • 8 Instituto de Investigaciones Biomédicas I+12, Hospital 12 de Octubre, Madrid, Spain.
  • 9 Neurooncology Unit, Unidad Funcional de Investigación en Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. psanchezg@isciii.es rgargini@isciii.es.
Abstract

The extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in tumor vessels, reinforcing the vascular architecture. It was recently revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves the efficiency of chemotherapy. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here we show that mutations in EGFR stimulate the capacity of glioma cells to function as pericytes in a BMX- (bone marrow and X-linked) and SOX9-dependent manner. Subsequent activation of platelet-derived growth factor receptor beta in the vessel walls of EGFR-mutant gliomas stabilized the vasculature and facilitated the recruitment of immune cells. These changes in the tumor microenvironment conferred a growth advantage to the tumors but also rendered them sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas were enriched in blood vessels, but showed a highly disrupted blood-brain barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which led to poor oxygenation, necrosis, and hypoxia. Overall, these findings identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relationship between the tumor cells and their vascular and immune milieu. Our results lay the foundations for a vascular-dependent stratification of gliomas and suggest different therapeutic vulnerabilities determined by the genetic status of EGFR. SIGNIFICANCE: This study identifies the EGFR-related mechanisms that govern the capacity of glioma cells to transdifferentiate into pericytes, regulating the vascular and immune phenotypes of the tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2142/F1.large.jpg.

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