Early clonal extinction in glioblastoma progression revealed by genetic barcoding

Glioblastoma progression in its early stages remains poorly understood. Here, we transfer PDGFB and genetic barcodes in mouse brain to initiate gliomagenesis and enable direct tracing of glioblastoma evolution from its earliest possible stage. Unexpectedly, we observe a high incidence of clonal extinction events and progressive divergence in clonal sizes, even after the acquisition of malignant phenotype. Computational modeling suggests these dynamics result from clonal-based cell-cell competition. Through bulk and single-cell transcriptome analyses, coupled with lineage tracing, we reveal that Myc transcriptional targets have the strongest correlation with clonal size imbalances. Moreover, we show that the downregulation of Myc expression is sufficient to drive competitive dynamics in intracranially transplanted gliomas. Our findings provide insights into glioblastoma evolution that are inaccessible using conventional retrospective approaches, highlighting the potential of combining clonal tracing and transcriptomic analyses in this field. [Display omitted] •Barcoding reveals massive clonal loss during early phases of gliomagenesis•Computational analysis suggests a clone-based competition as driver of clone loss•Myc and its targets are the most modulated signature during clonal purification•Myc perturbation in mouse glioma cells drives competitive dynamics in vivo Ceresa et al. reveal that in the early stages of glioma development, intercellular competition results in a massive extinction event, annihilating most initial cancer cell clones. The study showed that the competition is driven by the expression of Myc gene and its targets.