METB-02. Reconstructing the regulatory programs underlying the phenotypic plasticity of neural cancers

Nervous system cancers in both adults and children 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 and predicts key transcription factors and kinases that regulate each module in HGG_07we identify critical regulators of specific cell states and suggest interventions to improve the response to standard-of-care treatment. Additionally, our integrative analysis reveals meta-modules across brain tumor types, with shared function and regulation. As an example, we identify a meta-module regulated by SPI1 and IRF8 linked to an immune-mediated mesenchymal-like state in both glioblastoma and medulloblastoma patients. The algorithm is provided as an easy-to-use R package that facilitates the exploration of regulatory programs underlying cell plasticity.