Pathania Group Research Overview

Brain tumours are now the most common cancer in children less than 19 years of age, causing more deaths than any other childhood malignancy. Around half of all paediatric brain tumours are diagnosed as gliomas and ependymomas, with high-grade gliomas and hindbrain ependymomas having the poorest survival outcomes and limited or non-existent treatment options.

We have established a novel brain tumour modelling approach that delivers transposons into endogenous neural stem cells during foetal brain development. We used this to create the first molecularly and histologically faithful model of H3K27M-driven paediatric glioma (Pathania et al., Cancer Cell, 2017). This model enables exploration of biological mechanisms and therapeutic opportunities for a type of cancer in which human material is scarce. More generally, this work demonstrated for the first time that a mutation in a core chromatin component can drive brain tumours by stalling the normal development of discrete foetal progenitors and has implications for other brain tumour types in which epigenetic deregulation also occurs.

Since setting up the lab in 2019, we further developed 16 additional paediatric glioma models, driven by various combinations of histone mutations and partner alterations, that together recapitulate the genetic diversity of this heterogenous disease entity (McNicholas et al., Cancer Discovery, 2023). We used these models to identify tumour subtype-specific biology and opportunities for targeted therapy. Cell lines derived from these models are also uniquely capable of engrafting in immunocompetent, syngeneic recipients, making these the most suitable models for evaluating tumour-microenvironment (TME) interactions and immunotherapy approaches. Additionally, in collaboration with other groups we have extensively profiled the composition of the TME in paediatric glioma patient samples and compared this information to data from mouse models. We found that the models share a high degree of correspondence with human tumours (Andrade et al., Nature Communications, 2024). We also evaluated a novel combination therapy designed to increase the efficacy of checkpoint blockade. This significantly improved survival by substantially increasing lymphoid infiltration, demonstrating that the microenvironment can be therapeutically reprogrammed in these famously immunologically cold tumours.

Future work will explore 1) subtype-specific precision therapy development, by carrying out CRISPR and high content imaging-based phenotypic drug screens; 2) new drug targets in the microenvironment, by using flow cytometry, multiplex cyclic immunofluorescence, and spatial transcriptomics; and 3) the development of resistance, by using genetic barcoding and CRISPR screening approaches in immune-competent models, to reveal how standard treatments influence genetic dependencies and clonal trajectories, induce phenotype switching, and remodel the microenvironment.