Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85, Uppsala, Sweden.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Commun. 2024 Nov 9;15(1):9699. doi: 10.1038/s41467-024-53954-3.
Nervous system cancers exhibit diverse transcriptional cell states influenced by normal development, injury response, and growth. However, the understanding of these states' regulation and pharmacological relevance remains limited. Here we present "single-cell regulatory-driven clustering" (scregclust), a method that reconstructs cellular regulatory programs from extensive collections of single-cell RNA sequencing (scRNA-seq) data from both tumors and developing tissues. The algorithm efficiently divides target genes into modules, predicting key transcription factors and kinases with minimal computational time. Applying this method to adult and childhood brain cancers, we identify critical regulators and suggest interventions that could improve temozolomide treatment in glioblastoma. Additionally, our integrative analysis reveals a meta-module regulated by SPI1 and IRF8 linked to an immune-mediated mesenchymal-like state. Finally, scregclust's flexibility is demonstrated across 15 tumor types, uncovering both pan-cancer and specific regulators. The algorithm is provided as an easy-to-use R package that facilitates the exploration of regulatory programs underlying cell plasticity.
神经系统癌症表现出多种受正常发育、损伤反应和生长影响的转录细胞状态。然而，这些状态的调控和药理学相关性的理解仍然有限。在这里，我们提出了“单细胞调控驱动聚类”（scregclust）方法，该方法可以从肿瘤和发育组织的大量单细胞 RNA 测序（scRNA-seq）数据中重建细胞调控程序。该算法可以有效地将靶基因分成模块，以最小的计算时间预测关键的转录因子和激酶。将该方法应用于成人和儿童脑癌，我们确定了关键的调控因子，并提出了可能改善替莫唑胺治疗胶质母细胞瘤的干预措施。此外，我们的综合分析揭示了一个由 SPI1 和 IRF8 调控的、与免疫介导的间充质样状态相关的元模块。最后，scregclust 的灵活性在 15 种肿瘤类型中得到了证明，揭示了泛癌和特定的调控因子。该算法作为一个易于使用的 R 包提供，便于探索细胞可塑性的调控程序。
