This project takes a different approach to treating brain cancer by focusing on glioma stem cells rather than the bulk tumour. Conventional treatments often target rapidly dividing tumour cells, but fail to eliminate GSCs, which can survive therapy and regenerate the tumour. By isolating GSCs from fresh brain tumour tissues collected by the Brain Tumour Biobank and studying their molecular features in detail, this research aims to identify specific vulnerabilities in GSCs that can be targeted with new therapies.
Addressing tumour heterogeneity at its root may lead to more durable remissions and better outcomes for people with brain cancer.

If successful, this project could lead to therapies that specifically eliminate the small population of glioma stem cells responsible for tumour recurrence. This could improve long-term survival, reduce the risk of relapse, and offer patients treatments that are better tailored to the biology of their tumours. By improving our understanding of tumour heterogeneity and the role of GSCs, this project also has the potential to inform rational precision medicine strategies for brain cancer and beyond.

Diffuse gliomas remain a major therapeutic challenge due to extensive intra-tumour heterogeneity, where genetically and phenotypically distinct subpopulations coexist within a single tumour. Single-cell RNA sequencing from Projects A and B funded from CTF has revealed seven distinct malignant cell states that describe these adult glioma tumours. One of the key findings from this phylogenetic analysis was the identification of glioma stem cells (GSCs) as the root progenitor cells for the various malignant states within gliomas. Although GSCs represent only 5-12% of the overall malignant cells in these datasets, they play a pivotal role in driving tumour recurrence and treatment resistance. Given the central role that GSCs play in glioma progression, our current project seeks to isolate and validate these cells and uncover therapeutic strategies to target them specifically. We aim to isolate and validate GSCs using a combination of fluorescence-activated cell sorting and single-cell RNA sequencing. To gain deeper insights into the transcriptional landscape of GSCs, including alternative splicing events, we will integrate long-read nanopore sequencing. Furthermore, we will employ spatial transcriptomics to map the interactions between GSCs and other cell types within the tumour microenvironment. Finally, we aim to identify therapeutic vulnerabilities in GSCs through high-throughput drug screening, which will help us discover compounds that selectively target GSC-specific pathways, thereby preventing tumour recurrence and improving patient outcomes.

The overarching aims of this grant includes:

Aim 1: Optimisation of GSC Isolation and Molecular Characterisation

Aim 2: Functional Validation of GSCs and Spatial Characterisation

Aim 3: Identification of Therapeutic Vulnerabilities in GSCs