Spatial transcriptomics and multi-omics reveal relapse and resistance mechanisms of EndMT-derived CAFs mediated by TNC and FLNC in glioblastoma

作者：Ji Li, Die Xia, Yu Zhou, Yaling Hu, Zhenkun Yang, Ying Yin, Jingjing Wang, Bo Zhang, Lingli Gong, Koukou Li, Jian Zou, Mei Wang · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06743-5 · 被引用次数：13 · 研究领域：Glioma Diagnosis and Treatment、Proteoglycans and glycosaminoglycans research、Cell Adhesion Molecules Research

BACKGROUND: Chemoresistance and recurrence following treatment are the greatest impediments to the prognosis of glioblastoma (GBM). Increasing evidence indicates that cancer-associated fibroblasts (CAFs) play a significant role in the progression of glioblastoma. Nevertheless, the role and source of CAFs in recurrent and chemotherapy-resistant GBMs still remain ambiguous. METHODS: Spatial transcriptome (ST) sequencing was conducted on the tissue microarray encompassing primary and recurrent glioma samples in order to characterize the cellular composition. Subsequently, the infiltration of CAFs in our formerly established in vivo temozolomide (TMZ)-resistant model was inspected through immunohistochemical staining. Additionally, we carried out RNA-seq and label-free quantitation (LFQ) proteomics on HCMECs co-cultured with TMZ-sensitive (TMZ-S) or TMZ-resistant (TMZ-R) cells to explore the mechanism. RESULTS: This investigation revealed that CAFs and astrocytes are enriched in recurrent GBM, and this phenotype is associated with the expression of extracellular matrix (ECM) proteins associated with COL1A1 and FN1 deposition. Further investigations revealed that tenascin-C (TNC) and filamin C (FLNC), which potentially mediate endothelial-to-mesenchymal transition (EndMT), are the predominant factors that induce the deposition of ECM proteins in the resistance-promoting microenvironment. Additionally, the natural product punicalin (PNC) was found to downregulate EndMT-related prot...