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.

中文翻译：

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IDH-TAU-EGFR三联体定义了弥漫性神经胶质瘤的新生血管景观。

表达异柠檬酸脱氢酶1/2（IDH1 / 2）突变型的神经胶质瘤的预后要优于野生型（wt）IDH1 / 2神经胶质瘤。但是，这些突变（mut）蛋白如何影响肿瘤微环境仍然是一个悬而未决的问题。在这里，我们描述了微管相关蛋白TAU（MAPT）的转录，该基因已与神经退行性疾病经典地相关，在小鼠和人类神经胶质瘤中由wt和mut IDH1 / 2之间的平衡表观遗传控制。在IDH1 / 2 mut肿瘤中，我们发现TAU的高表达随肿瘤进展而降低。此外，带有表皮生长因子受体（EGFR）突变的肿瘤几乎不存在MAPT，而其转录与携带wt或扩增的（amp）EGFR的神经胶质瘤的总体存活率呈负相关。我们证明TAU的过表达通过稳定微管，通过阻断EGFR，核因子kappa损害了神经胶质瘤细胞的间质/周细胞样转化。 -B的轻链增强子（NF-κB）和具有PDZ结合基序的转录共激活子（TAZ）。我们的数据还显示，mut EGFR诱导了该途径的组成性激活，该途径不再对TAU敏感。通过抑制EGFRamp / wt肿瘤细胞的转分化能力，TAU蛋白抑制了血管生成并促进了血管正常化，降低了神经胶质瘤的侵袭性并提高了其对化学疗法的敏感性。通过阻断EGFR，活化B的核因子κ轻链增强子和具有PDZ结合基序的转录共激活因子（TAZ）来损害神经胶质瘤细胞的间充质/周细胞样转化。我们的数据还显示，mut EGFR诱导了该途径的组成性激活，该途径不再对TAU敏感。通过抑制EGFRamp / wt肿瘤细胞的转分化能力，TAU蛋白抑制了血管生成并促进了血管正常化，降低了神经胶质瘤的侵袭性并提高了其对化学疗法的敏感性。通过阻断EGFR，活化B的核因子κ轻链增强子和具有PDZ结合基序的转录共激活因子（TAZ）来损害神经胶质瘤细胞的间充质/周细胞样转化。我们的数据还显示，mut EGFR诱导了该途径的组成性激活，该途径不再对TAU敏感。通过抑制EGFRamp / wt肿瘤细胞的转分化能力，TAU蛋白抑制了血管生成并促进了血管正常化，降低了神经胶质瘤的侵袭性并提高了其对化学疗法的敏感性。对TAU不再敏感。通过抑制EGFRamp / wt肿瘤细胞的转分化能力，TAU蛋白抑制了血管生成并促进了血管正常化，降低了神经胶质瘤的侵袭性并提高了其对化学疗法的敏感性。对TAU不再敏感。通过抑制EGFRamp / wt肿瘤细胞的转分化能力，TAU蛋白抑制了血管生成并促进了血管正常化，降低了神经胶质瘤的侵袭性并提高了其对化学疗法的敏感性。