The isocitrate dehydrogenase (IDH1/2) mutations are frequent genetic abnormalities in the majority of WHO grade II/III glioma and secondary GBM. IDH1-mutated (IDH1^Mut) glioma exhibits distinctive patterns in cancer biology and metabolism. In the present study, we showed that bone morphogenetic proteins (BMP4) are significantly upregulated in IDH1^Mut glioma. Further, we demonstrated that cancer-associated BMP4 is secreted to tumor microenvironment, which enhances the tumor migration and invasion through an autocrine manner. Mechanistically, BMP4 activates its receptor and concomitant SMAD1/5/8 signaling, which potentiates Wnt/β-catenin signaling by enhancing Frizzled receptor expression. LDN-193189, a selective BMP receptor inhibitor, prolonged the overall survival of mice bearing IDH1-mutated intracranial xenografts by limiting BMP/catenin signaling. These findings demonstrate the pivotal role of BMP4 on tumor aggressiveness in IDH1^Mut gliomas, suggesting a possible therapeutic strategy for this type of malignancy.

在大多数WHO II / III级神经胶质瘤和继发性GBM中，异柠檬酸脱氢酶（IDH1 / 2）突变是常见的遗传异常。IDH1突变（IDH1 ^Mut）胶质瘤在癌症生物学和代谢中表现出独特的模式。在本研究中，我们显示IDH1 ^Mut中的骨形态发生蛋白（BMP4）显着上调胶质瘤。此外，我们证明了癌症相关的BMP4被分泌到肿瘤微环境中，从而通过自分泌方式增强了肿瘤的迁移和侵袭。机械上，BMP4激活其受体和伴随的SMAD1 / 5/8信号传导，通过增强卷曲蛋白受体的表达来增强Wnt /β-catenin信号传导。LDN-193189，一种选择性的BMP受体抑制剂，通过限制BMP / catenin信号传导，延长了携带IDH1突变的颅内异种移植物的小鼠的总体存活期。这些发现证明了BMP4在IDH1 ^Mut胶质瘤中对肿瘤侵袭性的关键作用，暗示了这种恶性肿瘤的可能治疗策略。