The study of tumor cell states and their spatial organization has gained significant attention, particularly in the context of diffuse midline gliomas (DMGs) with H3-K27M mutations. Liu et al. explored the heterogeneity of these tumors across different ages and anatomical locations, revealing that both intrinsic and extrinsic features of glioma cells are influenced by these factors. By employing single-cell transcriptomic, epigenomic, and spatial analyses, the researchers provided a comprehensive view of how the shared driver mutation manifests differently in pediatric versus adult populations, highlighting the need for age-specific therapeutic strategies (ref: Liu doi.org/10.1038/s41588-022-01236-3/). Furthermore, Wang et al. contributed to this theme by investigating glioblastoma (GBM) evolution under therapy. Their findings indicated that rather than genetic mutations, phenotype switching plays a critical role in tumor progression and therapy resistance. This study utilized single-cell lineage tracing to demonstrate the plasticity of GBM cells, suggesting that therapeutic approaches must account for this adaptability to improve treatment outcomes (ref: Wang doi.org/10.1038/s43018-022-00475-x/). Together, these studies underscore the complexity of tumor biology and the necessity for tailored interventions based on tumor cell states and their spatial dynamics.

Genomic alterations are pivotal in understanding the pathogenesis of gliomas, particularly in pediatric cases such as Juvenile Pilocytic Astrocytomas (JPAs). Zwaig et al. focused on the detection and genomic analysis of BRAF fusions, which are prevalent in JPAs and are linked to the aberrant activation of the MAPK signaling pathway. Their research combined multi-omic data to elucidate the mechanisms underlying these fusions, particularly the KIAA1549-BRAF fusion, which results in the loss of BRAF's auto-inhibitory domain and leads to constitutive kinase activation. This study also highlighted the challenges posed by the high vascularity and immune infiltration in JPAs, which can complicate the purity of tumor cell samples used for genomic analysis (ref: Zwaig doi.org/10.1186/s12885-022-10359-z/). The findings emphasize the importance of integrating various omics approaches to gain a comprehensive understanding of the genetic landscape of gliomas, which could inform future therapeutic strategies targeting these specific alterations.

The identification of therapeutic targets in glioblastoma (GBM) has been a focal point of recent research, particularly in light of the challenges posed by tumor heterogeneity and therapy resistance. Wang et al. provided insights into the evolution of GBM under therapeutic pressure, revealing that the lack of selection for specific DNA mutations in recurrent disease suggests a reliance on phenotype switching as a survival mechanism. Their single-cell lineage tracing approach demonstrated the high plasticity of GBM cells, indicating that traditional mutation-based targeting may not be sufficient for effective treatment (ref: Wang doi.org/10.1038/s43018-022-00475-x/). This study calls for a shift in therapeutic strategies towards understanding and targeting the dynamic cellular states of GBM, which could lead to more effective interventions. The findings from this research not only highlight the complexity of GBM but also pave the way for innovative approaches that consider the tumor's adaptive responses to therapy.