Neurooncology Unit, Unidad Funcional de Investigación en Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Facultad de Medicina, Universidad Francisco de Vitoria, Madrid, Spain.
Cancer Res. 2021 Apr 15;81(8):2142-2156. doi: 10.1158/0008-5472.CAN-20-3558. Epub 2021 Feb 16.
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 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 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 . 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.
胶质母细胞瘤细胞具有非凡的可塑性，使其能够在肿瘤血管中不同的细胞隔室中发挥作用，从而增强血管结构。最近发现，靶向代表侵袭性肿瘤中大部分壁细胞群体的胶质瘤衍生周细胞，可增加血管通透性并提高化疗效率。然而，这种转分化过程的分子决定因素尚未阐明。在这里，我们表明，突变可刺激胶质瘤细胞以 BMX-（骨髓和 X 连锁）和 SOX9 依赖的方式发挥周细胞的功能。随后，EGFR 突变型胶质母细胞瘤血管壁中血小板衍生生长因子受体β的激活稳定了血管，并促进了免疫细胞的募集。肿瘤微环境的这些变化赋予肿瘤生长优势，但也使它们对周细胞靶向分子（如伊布替尼或舒尼替尼）敏感。在没有突变的情况下，高级别神经胶质瘤富含血管，但由于 BMX/SOX9 激活和周细胞覆盖减少，导致血脑屏障高度破坏，从而导致缺氧、坏死和缺氧。总体而言，这些发现确定了 EGFR 突变是胶质母细胞瘤向周细胞转分化的关键调节因子，突出了肿瘤细胞与其血管和免疫微环境之间的复杂关系。我们的研究结果为基于血管的胶质瘤分层奠定了基础，并提示不同的治疗脆弱性取决于的遗传状态。意义：这项研究确定了 EGFR 相关机制，这些机制控制着胶质瘤细胞向周细胞转分化的能力，调节肿瘤的血管和免疫表型。图：http://cancerres.aacrjournals.org/content/canres/81/8/2142/F1.large.jpg。
