The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.

中文翻译：

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胶质母细胞瘤进化的综合蛋白质组学特征

胶质母细胞瘤（GBM）的进化轨迹是一个多方面的生物过程，超出了单纯的遗传改变的范围。在这里，我们对 123 对纵向胶质母细胞瘤进行了综合蛋白质组学分析，并通过激活复发性肿瘤中的神经元转变和突触发生途径来识别诊断和替代时的高度增殖细胞状态。蛋白质组学和磷酸化蛋白质组学分析表明，复发时向神经元状态的分子转变以无翼相关整合位点（WNT）/平面细胞极性（PCP）信号通路和BRAF蛋白激酶的翻译后激活为标志。一致地，患者来源的异种移植（PDX）模型的多组学分析反映了相似的进化轨迹模式。B-raf 原癌基因 (BRAF) 激酶的抑制会损害复发性肿瘤细胞的神经元转换和迁移能力，这是治疗后进展的表型标志。替莫唑胺 (TMZ) 与 BRAF 抑制剂维莫非尼的联合治疗可显着延长 PDX 模型的生存期。这项研究提供了对胶质母细胞瘤进化和治疗耐药性的生物学机制的全面见解，突出了有前景的临床干预治疗策略。