Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma

• Published in: Cell reports (Cambridge) 2025-01, Vol.44 (1), p.115149, Article 115149
• Main Authors: Licón-Muñoz, Yamhilette, Avalos, Vanessa, Subramanian, Suganya, Granger, Bryan, Martinez, Frank, García-Montaño, Leopoldo A., Varela, Samantha, Moore, Drew, Perkins, Eddie, Kogan, Michael, Berto, Stefano, Chohan, Muhammad O., Bowers, Christian A., Piccirillo, Sara G.M.
• Format: Article
• Language: English
• Subjects: Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; brain tumors; cancer stem-like cells; Cell Nucleus - metabolism; CP: Cancer; Gene Expression Regulation, Neoplastic; glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Interleukin-1beta - metabolism; Lateral Ventricles - metabolism; Lateral Ventricles - pathology; Male; Microglia - metabolism; Microglia - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; sub-ventricular zone; Tumor Microenvironment; Wnt-5a Protein - genetics; Wnt-5a Protein - metabolism; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.115149

The sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and the emergence of recurrence. Here, we build a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass and the SVZ of 15 patients and two histologically normal SVZ samples as controls. We identify a ZEB1-centered mesenchymal signature in the tumor cells of the SVZ. Moreover, the SVZ microenvironment is characterized by tumor-supportive microglia, which spatially coexist and establish crosstalks with tumor cells. Last, differential gene expression analyses, predictions of ligand-receptor and incoming/outgoing interactions, and functional assays reveal that the interleukin (IL)-1β/IL-1RAcP and Wnt-5a/Frizzled-3 pathways represent potential therapeutic targets in the SVZ. Our data provide insights into the biology of the SVZ in patients with GBM and identify potential targets of this microenvironment. [Display omitted] •The SVZ of patients with GBM is characterized by a ZEB1-centered mesenchymal signature•Microglia of the SVZ represent the majority of TAMs and spatially coexist with tumor cells•Microglia interact with tumor cells in the SVZ through IL-1β/IL-1RAcP and Wnt-5a/Frizzled-3•IL-1β/IL-1RAcP and Wnt-5a/Frizzled-3 represent potential therapeutic targets in the SVZ Licón-Muñoz et al. built a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass and the sub-ventricular zone (SVZ) of 15 patients with GBM. They identify a mesenchymal signature and tumor-supportive microglia that establish cell-to-cell interactions with tumor cells in the SVZ through IL-1β/IL-1RAcP and Wnt-5a/Frizzled-3, representing potential targets for GBM treatment.