Bioinformatics analysis of MMP14+ myeloid cells affecting endothelial-mesenchymal transformation and immune microenvironment in glioma

Abstract

Background

Gliomas, known for their complex and aggressive characteristics, are deeply influenced by the tumor microenvironment. Matrix metalloproteinases (MMPs) play a vital role in shaping this environment, presenting an opportunity for novel treatment strategies.

Methods

We collected six bulk RNA datasets, one single-cell RNA sequencing (scRNA-seq) dataset, and gene sets related to Matrix Metalloproteinases (MMPs), Endothelial-Mesenchymal Transformation (EndMT), and sprouting angiogenesis. We computed enrichment scores using Gene Set Variation Analysis (GSVA) and Single-sample Gene Set Enrichment Analysis (ssGSEA). To analyze immune infiltration, we employed the CIBERSORT method. Data analysis techniques included the log-rank test, Cox regression, Kruskal-Wallis test, and Pearson correlation. For single-cell data, we utilized tools such as Seurat and CellChat for dimensionality reduction, clustering, and cell communication analysis.

Results

1. MMP14 was identified as an independent prognostic marker, highly expressed in myeloid cells in recurrent glioblastoma, highlighting these cells as functionally significant. 2. C–C Motif Chemokine Ligand (CCL) signaling from MMP14+ myeloid cells was identified as a critical immune regulatory pathway, with high C–C Motif Chemokine Receptor 1 (CCR1) expression correlating with increased M2 macrophage infiltration and PD-L1 expression. 3. Patients with high MMP14 expression showed better responses to bevacizumab combined chemotherapy. 4. Signaling pathways involving Visfatin, VEGF, and TGFb, emanating from myeloid cells, significantly impact endothelial cells. These pathways facilitate EndMT and angiogenesis in gliomas. 5. Nicotinamide Phosphoribosyltransferase (NAMPT) showed a strong link with angiogenesis and EndMT, and its association with chemotherapy resistance and differential sensitivity to bevacizumab was evident.

Conclusions

MMP14+ myeloid cells are critical in promoting tumor angiogenesis via EndMT and in mediating immunosuppression through CCL signaling in glioblastoma. MMP14 and NAMPT serve as vital clinical indicators for selecting treatment regimens in recurrent glioma. The study suggests that a combined blockade of CCR1 and CD274 could be a promising therapeutic strategy.