Diffuse midline glioma is an aggressive and incurable brain tumour that most commonly presents in children. It has a dismal prognosis – most children die within 18 months.
Dr Pathania’s project studied genetic mutations commonly found in diffuse midline gliomas, and has made important progress in our understanding of how these tumours develop, how they interact with the immune system, and how they might respond to different treatments.
Diffuse midline glioma (DMG) is a very aggressive and variable type of children's brain tumour.
Until recently, these tumours were thought to be mostly restricted to the brain stem, and were known as 'diffuse intrinsic pontine glioma' or 'DIPG'. Knowledge has advanced rapidly in recent years, and we now know that this type of tumour can extend from the brainstem, up the middle part of the brain (the midline), and into the frontal lobes in some cases. This has given rise to the new name of diffuse midline glioma. Although the name is new, DIPG and DMG are the same type of tumour.
Whilst our understanding of these tumours continues to advance, we haven't yet reached the stage where we have effective treatments for DMG. The diffuse nature of DMGs, combined with their critical location, means that surgical removal is usually not possible. Chemotherapies used to treat other forms of glioma are ineffective in DMG. Radiotherapy is used to slow their growth but is not curative.
To improve the outlook for children with DMG it is essential that we develop new therapies that target the unique biology of these tumours.
Read more: About brain tumours
Genetic sequencing has revealed that DMGs represent several distinct tumour types – based on the different constellations of mutations they carry and where they occur in the brain. However, the relevance of many of these extra mutations is unknown – they may be present in tumours, but what do they do? Are they required for tumour growth? And how important are they for treatment? Dr Pathania and his team explored these questions via three interlinked studies.
In the first study, the team created 16 new mouse models of paediatric high-grade gliomas that accurately mimic the diversity seen in human tumours – appearing in different brain regions, at different ages, and growing at different speeds. The team then tested various treatments, and found that different tumour subtypes responded to different drugs. This work shows that treatments could be customised based on a tumour’s specific mutations, helping move toward more personalised and effective care for children.
The second study focused on the immune environment around these brain tumours – an area that hasn’t been well studied in paediatric cancers. Dr Pathania and his team found that these tumours have lots of myeloid immune cells (such as macrophages) but very few T cells, which are key fighters in the immune system. The team then applied a combination of drugs that target both the macrophages and the proteins that block immune activity, and found that tumour growth slowed down as a result. This opens the door to new immunotherapy strategies for treating childhood brain tumours.
Finally, in the third study the team looked at a rare and aggressive tumour called NB FOXR2, which is difficult to diagnose because it has features of both nerve and support cells in the brain. By comparing tumour cells to normal brain development, the team discovered that this tumour likely comes from a very specific type of early brain cell marked by the genes LHX6 and DLX. This discovery helps explain where these tumours come from and provides a valuable model for studying the disease and testing treatments.
DMG is a devastating form of brain cancer that has no effective treatment. New treatments are desperately needed.
Taken together, the three studies outlined above offer powerful new tools and insights into how paediatric brain tumours start, grow, and might be treated more effectively in the future, offering new hope to those affected by this terrible tumour.
Jessa, S., De Cola, A., Chandarana, B., McNicholas, M., Hébert, S., Ptack, A., Faury, D., Tsai, J. W., Korshunov, A., Phoenix, T. N., Ellezam, B., Jones, D. T. W., Taylor, M. D., Bandopadhayay, P., Pathania, M., Jabado, N., & Kleinman, C. L. (2025). FOXR2 Targets LHX6+/DLX+ Neural Lineages to Drive Central Nervous System Neuroblastoma. Cancer research, 85(2), 231–250. https://doi.org/10.1158/0008-5472.CAN-24-2248
Andrade, A. F., Annett, A., Karimi, E., Topouza, D. G., Rezanejad, M., Liu, Y., McNicholas, M., Gonzalez Santiago, E. G., Llivichuzhca-Loja, D., Gehlhaar, A., Jessa, S., De Cola, A., Chandarana, B., Russo, C., Faury, D., Danieau, G., Puligandla, E., Wei, Y., Zeinieh, M., Wu, Q., … Jabado, N. (2024). Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumour-promoting function. Nature communications, 15(1), 7769. https://doi.org/10.1038/s41467-024-52096-w
McNicholas, M., De Cola, A., Bashardanesh, Z., Foss, A., Lloyd, C. B., Hébert, S., Faury, D., Andrade, A. F., Jabado, N., Kleinman, C. L., & Pathania, M. (2023). A Compendium of Syngeneic, Transplantable Paediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities. Cancer discovery, 13(7), 1592–1615. https://doi.org/10.1158/2159-8290.CD-23-0004
Jessa, S., Mohammadnia, A., Harutyunyan, A. S., Hulswit, M., Varadharajan, S., Lakkis, H., Kabir, N., Bashardanesh, Z., Hébert, S., Faury, D., Vladoiu, M. C., Worme, S., Coutelier, M., Krug, B., Faria Andrade, A., Pathania, M., Bajic, A., Weil, A. G., Ellezam, B., Atkinson, J., … Kleinman, C. L. (2022). K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas. Nature genetics, 54(12), 1865–1880. https://doi.org/10.1038/s41588-022-01205-w
Chen, C. C. L., Deshmukh, S., Jessa, S., Hadjadj, D., Lisi, V., Andrade, A. F., Faury, D., Jawhar, W., Dali, R., Suzuki, H., Pathania, M., A, D., Dubois, F., Woodward, E., Hébert, S., Coutelier, M., Karamchandani, J., Albrecht, S., Brandner, S., De Jay, N., … Jabado, N. (2020). Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis. Cell, 183(6), 1617–1633.e22. https://doi.org/10.1016/j.cell.2020.11.012
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