Endothelial cells sense temozolomide resistance to facilitate monocyte-derived macrophage infiltration in glioblastoma

作者：Wei Gao, Jianliang Huang, Kun Deng, Xiang Lin, Xinmiao Long, Xuetong Li, Meng Huang, Xiangyu Wang, Xiaoling She, Qing Liu, Minghua Wu · 发表于：Drug Resistance Updates · 年份：2025 · DOI：10.1016/j.drup.2025.101329 · 被引用次数：9 · 研究领域：Glioma Diagnosis and Treatment、Immune cells in cancer、Cell Adhesion Molecules Research

AIMS: Glioblastoma (GBM), particularly mesenchymal and recurrent GBM, often develops resistance to temozolomide (TMZ) and is characterized by extensive infiltration of monocyte-derived macrophages (MDM), which contributes to treatment failure. However, the mechanisms through which TMZ-resistant GBM recruits MDM remain poorly understood. This study aims to investigate the molecular drivers of MDM infiltration in the context of TMZ resistance and to identify potential therapeutic targets to disrupt this process. METHODS: Patient-derived GBM organoid (GBO) was utilized as a model system. We performed molecular profiling to identify genes upregulated in TMZ-resistant recurrent GBO. Endothelial cells (ECs) cultures and preclinical GBM models were used to examine disruption of tight junctions and monocyte infiltration. Mechanistic studies employed genetic knockdown, pharmacological inhibition, and assays, including Chromatin immunoprecipitation-quantitative PCR, Western blot, and immunostaining, to validate pathway activity and protein interactions. RESULTS: COL6A1 (Collagen type VI alpha 1 chain) was significantly upregulated in TMZ-resistant recurrent GBO and associated with poor survival. COL6A1 is bound to ITGB1 (Integrin beta-1) on ECs, leading to disruption of tight junctions via UBD (Ubiquitin-like modifier D)-mediated degradation of claudin-5. Furthermore, COL6A1 activated the FAK/SRC/Hippo/YAP signaling axis, which promoted lactylation of the transcription factor IKZF1 (IK...