Whilst typically benign, a subset of meningiomas displays aggressive and recurrent behavior. There is a paucity of reliable treatment options for this subset of patients and a relative lack of consensus on how to best manage these patients. This clinical challenge reflects underlying molecular complexity, driven byNF2,TRAF7, andCDKN2A/Bmutations alongside pervasive epigenetic dysregulation. High-throughput molecular profiling studies have proposed biologically distinct meningioma subgroups with varying clinical trajectories and therapeutic vulnerabilities. Distinct cell lineages of meningeal precursors are now appreciated to be essential in the establishment of the meninges. The numerous cellular lineages involved in meningeal development, the heterogeneity of meningioma location and (epi)genomic behavior, and the variability in its clinical and radiological manifestations raise the question of what critical insights can be gained by understanding meningeal development during embryogenesis to understand meningioma tumorigenicity. The current paper examines this paradigm by highlighting spatially linked mechanisms of anaplasia and treatment resistance, including the role of neural crest-derived convexity meninges in promoting dedifferentiation via YAP/TAZ signaling and mesoderm-derived skull base regions in maintainingTRAF7-mediated vulnerabilities. We further elucidate the emerging synthetic lethal paradigms, CRISPR-enabled target discovery, and PROTAC-mediated degradation strategies that may transform the therapeutic landscape of clinically challenging meningiomas driven by complex oncogenic circuitry. By bridging embryogenesis, spatial genomics, and molecular targeting, we propose a developmentally informed, lineage-stratified model for advancing precision therapeutics in high-grade and recurrent meningiomas.
尽管脑膜瘤通常为良性，但其中一部分表现出侵袭性和复发倾向。针对这部分患者，目前缺乏可靠的治疗方案，且在最佳管理策略上共识不足。这一临床挑战反映了其内在的分子复杂性，主要由NF2、TRAF7和CDKN2A/B基因突变及广泛的表观遗传失调驱动。高通量分子谱研究已提出具有不同临床进程和治疗脆弱性的生物学特征各异的脑膜瘤亚群。目前研究认识到，脑膜前体细胞的不同谱系对脑膜的形成至关重要。参与脑膜发育的多种细胞谱系、脑膜瘤位置与（表观）基因组行为的异质性，以及其临床和影像学表现的多样性，引发了一个关键问题：通过理解胚胎发生过程中的脑膜发育，我们能获得哪些重要启示以理解脑膜瘤的肿瘤发生机制？本文通过强调空间关联的间变与治疗抵抗机制来探讨这一范式，包括神经嵴来源的凸面脑膜通过YAP/TAZ信号通路促进去分化，以及中胚层来源的颅底区域维持TRAF7介导的脆弱性。我们进一步阐述了新兴的合成致死范式、CRISPR技术驱动的靶点发现以及PROTAC介导的降解策略，这些可能改变由复杂致癌网络驱动的临床难治性脑膜瘤的治疗格局。通过整合胚胎发生、空间基因组学和分子靶向，我们提出了一个基于发育生物学、按细胞谱系分层的模型，以推动高级别和复发性脑膜瘤的精准治疗发展。
肿瘤(癌症)患者之家