NFAM1 organizes a lipid raft–restricted DAPP1–PLCG2 module to drive M2-like GAM polarization via Ca²⁺–NFAT1 signaling in glioma

NFAM1 组装脂筏限制性 DAPP1–PLCG2 模块并通过 Ca²⁺–NFAT1 信号通路驱动胶质瘤中 M2 样 GAM 极化

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ID: 330771
2026
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Abstract
Abstract Background Glioma-associated macrophages (GAMs) promote glioma progression, but the membrane-proximal mechanisms sustaining their tumor-supportive states remain poorly defined. Methods Bulk and single-cell transcriptomic analyses, human glioma specimens, GAM models, and orthotopic glioma models were used to define the expression and function of NFAM1. Lipid-raft fractionation, co-immunoprecipitation, proximity ligation, domain-mutant rescue, IP3 and Ca²⁺ measurements, and NFAT1 nuclear translocation assays delineated its signaling mechanism. Pharmacological, macrophage-depletion/reconstitution, and inducible genetic models evaluated its therapeutic relevance. Results NFAM1 was enriched in monocyte-derived, M2-like GAMs and associated with higher glioma grade, IDH-wild-type status, and poor survival. NFAM1 promoted GAM migration and M2-like polarization, thereby enhancing mesenchymal plasticity of glioma stem cells (GSCs), angiogenesis, and glioma progression. Mechanistically, phosphorylated NFAM1 recruited DAPP1 and PLCG2 through ITAM–SH2-dependent interactions within lipid rafts, organizing a spatially coordinated and functionally ordered signaling module. DAPP1 acted upstream of PLCG2 to promote IP3 production, Ca²⁺ signaling, and NFAT1 nuclear translocation. Madecassoside showed ITAM-dependent cellular target engagement with NFAM1, disrupted this signaling module, suppressed tumor-supportive GAM phenotypes, reduced orthotopic tumor growth, and prolonged survival. Its antitumor activity was markedly diminished after peripheral macrophage depletion or reconstitution with NFAM1-deficient bone marrow-derived macrophages. Moreover, inducible NFAM1 knockdown in reconstituted BMDM-derived GAMs after tumor establishment reduced tumor burden and extended survival. Conclusions NFAM1 spatially organizes lipid-raft-restricted DAPP1–PLCG2–Ca²⁺–NFAT1 signaling in monocyte-derived GAMs and represents a therapeutically targetable vulnerability in glioma.
摘要 背景 胶质瘤相关巨噬细胞（GAMs）促进胶质瘤进展，但维持其促肿瘤状态的膜近端机制仍不明确。 方法 利用Bulk与单细胞转录组分析、人脑胶质瘤标本、GAM模型及原位胶质瘤模型明确NFAM1的表达与功能。通过脂筏分级分离、免疫共沉淀、邻位连接实验、结构域突变回复实验、IP3与Ca²⁺检测以及NFAT1核易位实验阐明其信号转导机制。通过药理学模型、巨噬细胞清除/重建模型以及可诱导基因工程模型评估其治疗价值。 结果 NFAM1在单核细胞来源的M2样GAMs中高度富集，且与胶质瘤的高级别、IDH野生型状态以及不良预后显著相关。NFAM1促进GAM迁移及M2样极化，进而增强胶质瘤干细胞（GSCs）的间质可塑性、血管生成及胶质瘤进展。机制上，磷酸化的NFAM1在脂筏内通过依赖ITAM–SH2结构域的相互作用招募DAPP1和PLCG2，构建起空间协调且功能有序的信号模块。DAPP1位于PLCG2上游，促进IP3生成、Ca²⁺信号传导及NFAT1核易位。羟基积雪草苷（Madecassoside）展现出对NFAM1的ITAM依赖性细胞靶向结合，破坏了该信号模块，抑制了促肿瘤性GAM表型，减缓了原位肿瘤生长并延长了生存期。在外周巨噬细胞被清除或用NFAM1缺陷型骨髓来源巨噬细胞（BMDMs）重建后，其抗肿瘤活性显著减弱。此外，在成瘤后可诱导敲低重建BMDM来源GAMs中的NFAM1，可减轻肿瘤负荷并延长生存期。 结论 NFAM1在单核细胞来源的GAMs中空间组织了局限于脂筏的DAPP1–PLCG2–Ca²⁺–NFAT1信号轴，代表了胶质瘤中一个具有治疗潜力的可靶向弱点。
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Authors Yaochuan Zhang, Rongjin Chen, Yifu Song, Yibin Lin, Xu Cao, 田国峰, Xiaodi Han, Lin Zong, 于涓瀚, Li Zhang, Sheng Han
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Journal journal of neuro-oncology
Year 2026
DOI
10.1093/neuonc/noag240
URL
https://doi.org/10.1093/neuonc/noag240
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