A new study has revealed a detailed map of the genes, proteins, infiltrating cells and signalling pathways involved in driving an aggressive brain tumour – glioblastoma.
Glioblastoma is the most common primary malignant brain tumour and also the most aggressive nervous system cancer. Every year in the US there are 12,000 new cases. Moreover, the disease has a median survival under 2 years.
The Cancer Genome Atlas and other projects have shaped the WHO classification of nervous system tumours to incorporate molecular features. Glioblastoma is categorised as either IDH-wild type (IDH-WT; ~ 90%) or IDH-mutant (~10%). IDH-WT glioblastomas fall specifically into three distinct subclasses -proneural, classical and mesenchymal – based on genomic alterations and gene expression signatures.
While surgical resection, chemotherapy and radiotherapy remain the standard of care, promising immunotherapies have recently emerged. Understanding the molecular pathogenesis of glioblastoma is crucial to improving diagnosis and treatment.
Generating a detailed map
In this study, published in Cancer Cell, researchers integrated proteogenomic and metabolomic data to investigate 99 treatment-naïve glioblastomas. This research forms part of the Clinical Proteomic Tumour Analysis Consortium (CPTAC).
The team identified key phosphorylation events – phosphorylated PTPN11 and PLCG1 – as potential switches mediating oncogenic pathway activation. They also revealed gene expression patterns that are involved in the epithelial-to-mesenchymal transmission and determined how acetylation may explain some functional differences between glioblastoma subtypes.
Additionally, the team also identified four different categories to classify glioblastoma, which may influence whether the tumour will respond to targeted therapies. Type 1 tumours contain high numbers of macrophages and a few T cells. Tumours that are type 2 have a moderate number of macrophages. Type 3 tumours include high numbers of T cells and a few macrophages. Finally, type 4 tumours have few or no immune cells of any type.
This work highlights biological relationships that may contribute to stratification of glioblastoma patients for more effective responses to immune therapies.
Image credit: By kjpargeter – www.freepik.com