Gliomagenesis mimics an injury response orchestrated by neural crest-like cells

To explore the early steps in glioma formation, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging to initiate and then closely track tumour formation. We isolated labeled and unlabeled cells at multiple stages -- before the first visible abnormality, at the time of the first visible lesion, and then through the stages of tumour growth -- and subjected each stage to single-cell profiling. We identify a malignant cell state with a neural crest-like gene expression signature that is highly abundant in the early stages, but relatively diminished in the late stage of tumour growth. Genomic analysis based on the presence of copy number alterations suggests that these neural crest-like states exist as part of a heterogenous clonal hierarchy that evolves with tumour growth. By exploring the injury response in the wounded normal mouse brain, we identify cells with a similar signature that emerge following injury and then disappear over time, suggesting that activation of an injury response programme occurs during tumourigenesis. Indeed, our experiments reveal a non-malignant injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells. Collectively, our findings provide insight into the early stages of gliomagenesis, identifying a unique stem cell-like state and an injury response programme tied to early tumour formation. This will have implications on glioblastoma therapies and raises exciting new possibilities for early disease diagnosis and prevention. Some of the data in this series can also be explored through the following App link: gbm.stem-cells.ca.