KEY TAKEAWAYS
- The study aimed to explore the pathological mechanisms of anoikis-mediated TME in GBM.
- The results showed that BRMS1+ microglial cells could be potential therapeutic targets in GBM’s immunosuppressive microenvironment.
Anoikis, a form of programmed cell death triggered by loss of cell adhesion to the extracellular matrix (ECM), plays a crucial role in brain cancer. Resistance to anoikis is a key indicator of cancer cell invasion, metastasis, therapy resistance, and recurrence.
While research has uncovered several factors regulating anoikis resistance, the pathological mechanisms of the anoikis-mediated tumor microenvironment (TME) in glioblastoma (GBM) remain largely unexplored.
The study utilized single-cell RNA sequencing (scRNA-seq) data combined with non-negative matrix factorization (NMF) to identify and characterize TME cell clusters with distinct anoikis-associated gene signatures. Prognostic and therapeutic response analyses were conducted using data from TCGA and CGGA datasets to evaluate the clinical significance of these TME cell clusters.
The spatial relationship between BRMS1+ microglia and tumor cells was inferred using spatial transcriptome RNA sequencing (stRNA-seq) data. To simulate the tumor immune microenvironment, co-culture experiments were performed with microglia (HMC3) and GBM cells (U118/U251), with microglia transfected using a BRMS1 overexpression lentivirus. BRMS1, M2 macrophage-specific markers, PI3K/AKT signaling proteins, and apoptosis-related proteins were detected using Western blot or ELISA.
Tumor cell proliferation and apoptosis were evaluated using CCK-8, colony formation, and apoptosis assays, while invasive and migratory abilities were assessed using Transwell assays.
The results showed that NMF-based analysis successfully identified CD8+ T cell and microglia cell clusters with distinct gene signature characteristics. Trajectory analysis, cell communication, and gene regulatory network analyses collectively indicated that anoikis-mediated TME cell clusters could influence tumor cell development through various mechanisms.
Notably, BRMS1+ AP-Mic exhibited an M2 macrophage phenotype and had significant cell communication with malignant cells. High expression of BRMS1+ AP-Mic in TCGA and CGGA datasets was linked to poorer survival outcomes, highlighting its negative impact on immunotherapy.
The upregulation of BRMS1 in microglia may induce M2 macrophage polarization, activate the PI3K/AKT signaling pathway through SPP1/CD44-mediated cell interactions, inhibit tumor cell apoptosis, and promote tumor proliferation and invasion.
The study concluded that NMF-based analysis revealed the significant predictive value of anoikis-regulated TME in GBM for both prognosis and immunotherapeutic response. BRMS1+ microglial cells offer a new perspective for understanding the immunosuppressive microenvironment in GBM and could potentially serve as therapeutic targets in the future.
Funding support was provided by the Wuxi Taihu Lake Talent Plan, Supports for Leading Talents in Medical and Health Profession, and the Wuxi Health Care Commission Young and Middle-aged Top Talent Grant Program .
Source: https://link.springer.com/article/10.1007/s11060-024-04781-5
Zhao S, Ni K, Xie J, et al. (2024). “Exploring the prognostic value of BRMS1+ microglia based on single-cell anoikis regulator patterns in the immunologic microenvironment of GBM.” J Neurooncol. 2024. doi:10.1007/s11060-024-04781-5
