A single-cell based precision medicine approach using glioblastoma patient-specific models

Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multimodal single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multimodal data with single cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that regulate subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches in a concurrent, neo-adjuvant, or recurrent setting. SummaryInference of mechanistic drivers of therapy-induced evolution of glioblastoma at single cell resolution using RNA-seq and ATAC-seq from patient samples and model systems undergoing standard-of-care treatment informs strategy for identification of tumor evolutionary trajectories and possible cell state-directed therapeutics.