García-Vicente Laura, Martínez-Fernández María, Borja Michael, Tran Vanessa, Álvarez-Vázquez Andrea, Flores-Hernández Raquel, Ding Yuxin, González-Sánchez Raúl, Granados Alejandro, McGeever Erin, Kim Yang-Joon, Detweiler Angela, Mekonen Honey, Paul Sheryl, Pisco Angela O, Neff Norma F, Tabernero Arantxa
Neuroscience Institute of Castile-Leon (INCYL), iBRAINS-IN-CyL, Department of Biochemistry and Molecular Biology, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
Chan Zuckerberg Biohub, San Francisco, USA.
Commun Biol. 2025 Apr 28;8(1):671. doi: 10.1038/s42003-025-08092-x.
Different glioblastoma (GBM) subtypes have been identified based on the tumor microenvironment (TME). The discovery of new therapies for these hard-to-treat tumors requires a thorough characterization of preclinical models, including their TME, to apply preclinical results to the most similar GBM subtype. Using single-nucleus RNA sequencing (snRNA-seq), we characterized the tumor and TME in an immunocompetent mouse model with intracranially implanted GBM stem cells at different stages and treatments. Visium spatial transcriptomics confirmed the location of annotated cells. This model exhibits GBM targets related to integration into neural circuits - Grik2, Nlgn3, Gap43 or Kcnn4-, immunoevasion - Nt5e, Cd274 or Irf8- and immunosuppression - Csf1r, Arg1, Mrc1 and Tgfb1. The landscape of cytokines, checkpoint ligands and receptors uncovered Mrc1, PD-L1, TIM-3 or B7-H3, among the immunotherapy targets that can be addressed in this model. The comparison with human GBMs unveiled crucial similarities with TME GBM, the most frequent subtype.
基于肿瘤微环境（TME）已鉴定出不同的胶质母细胞瘤（GBM）亚型。要为这些难以治疗的肿瘤开发新疗法，需要全面表征临床前模型，包括其肿瘤微环境，以便将临床前结果应用于最相似的GBM亚型。我们使用单核RNA测序（snRNA-seq），对一个免疫活性小鼠模型中的肿瘤和肿瘤微环境进行了表征，该模型在不同阶段和治疗条件下颅内植入了GBM干细胞。Visium空间转录组学证实了注释细胞的位置。该模型展现出与整合到神经回路相关的GBM靶点——Grik2、Nlgn3、Gap43或Kcnn4，免疫逃逸靶点——Nt5e、Cd274或Irf8，以及免疫抑制靶点——Csf1r、Arg1、Mrc1和Tgfb1。细胞因子、检查点配体和受体图谱揭示了该模型中可针对的免疫治疗靶点，包括Mrc1、PD-L1、TIM-3或B7-H3。与人类GBM的比较揭示了与最常见的TME GBM亚型的关键相似之处。
