2023 Entry Clinical Fellowship
Delineating glioblastoma cell state transitions during cell invasion using a patient-derived glioblastoma ex vivo organoid model (GBO)
Glioblastoma is the most common primary malignant tumour of the central nervous system. It remains rapidly fatal, with a 6.8% 5-year survival rate. More than 40 clinical trials have failed to show a survival benefit. Therefore, it is a disease of unmet clinical need. Glioblastoma demonstrates genetic and transcriptional heterogeneity within and between tumours. Single-cell data show that within the tumour, there is a spectrum of cell identities reminiscent of neurodevelopmental lineages- neural progenitor-like, oligodendrocyte progenitor-like, astrocyte-like. However, there is also a mesenchymal or injury response state which is distinct compared to what’s found in development. The injury response state seems to arise in response to and continues to recruit myeloid cell lineages – bone marrow-derived macrophages and resident microglia. Recent data suggest an end cellular state responsible for tumour invasion determined by specific myeloid cell–cancer cell interactions. How do we capture glioma cancer cells' interaction with the myeloid cell microenvironment? Cell line cultures are not enough!
Jacob et al. 2020 developed a glioblastoma organoid, enabling to study of 3D myeloid-cancer cell interactions, retaining myeloid stem cells for up to 2 weeks and demonstrating transcriptional heterogeneity at the single-cell level, similar to the parental tumour. We aim to generate and use the model to study cancer cell invasion. We will label cells with a fluorescent tag and extract invading cells to understand how neural development versus injury response impact the biology of cell invasion. We now have targets that we can block to prevent this process. We will use this model to halt cell invasion.