Dissecting the Cellular and Molecular Origins of WNT-Medulloblastomas

Background

Medulloblastoma is the most common malignant childhood brain tumour.  Accounting for about 20% of all childhood brain tumours, medulloblastoma occurs most often in children younger than 16 years. Classified as a malignant embryonal hindbrain tumour, the disease displays various histological forms including classic, nodular anaplastic and large-cell tumours¹. Histology can differentiate medulloblastoma from other hindbrain tumours, but it is of limited value in predicting outcome or understanding tumour biology.

The combined efforts of our group and international collaborators have identified four subtypes of medulloblastoma that display distinct patterns of gene expression, DNA copy number alteration, and clinical behaviour (WNT, Sonic Hedgehog [SHH], Group-3 and Group-4)².  Despite these differences, all medulloblastomas are treated with the same combination of surgery, radiation, and chemotherapy.  This ‘blanket’ treatment fails to cure the majority of children with the most aggressive medulloblastomas (Group-3), and inflicts debilitating, long-term side effects on children with the most curable form (WNT subtype).  Therefore, future efforts to cure all children with medulloblastoma must provide an understanding of disease biology that can guide the development of curative, relatively non-toxic, subtype-specific therapies.  To this end, our group is focusing on understanding the origins and biology of the most curable form of medulloblastoma: WNT medulloblastoma.  By studying this subtype we hope to unmask the basis of this tumours susceptibility to therapy since this knowledge may be applied to render the more resistant variants more curable.

Figure 1: Ultrastructural phenotype of mWnt- medulloblastoma endothelium demonstrating abnormal fenestrations (holes in the vessel wall) and an absent blood brain barrier. Electron microscopy (EM) of endothelium in mWnt-medulloblastoma. Note regular fenestrations in mWnt-medulloblastomas on 3D scanning EM.

Current research

Using an innovative, cross-species genomics approach we have mapped the cell of origin of WNT-medulloblastoma to progenitor cells of the lower rhombic lip (LRLPs), thereby generating the first murine model of the disease, and demonstrating that subtypes of medulloblastoma are intrinsically different entities with distinct origins³. Additionally, using whole genome sequencing (WGS), we identified 41 novel, recurrent, mutations that affect different subtypes of human medulloblastoma⁴.  These mutations target regulators of H3K27 trimethylation in Group-3 and a new candidate oncogene and potential therapeutic target, DDX3X, in 50% of WNT and 12% of SHH-subtype medulloblastomas. We are now focusing on: (1) Understanding the role of mutant DDX3X in medulloblastoma and its relevance as a therapeutic target; (2) Identifying a comprehensive set of less toxic treatments for WNT-medulloblastoma by studying targetable cell signals that maintain this disease; (3) Conducting accurate preclinical trials of new treatments that combine neurosurgical, radiation and chemotherapeutic approaches. (4) Analysing the tumour microenvironment to understand why WNT-medulloblastoma, is so curable.  Most recently we have demonstrated that these tumours have no blood brain barrier and are therefore exposed to very high levels of chemotherapy (Figure 1).

Further Reading

1. Patmore DM, Jassim A, Nathan E, et al. DDX3X Suppresses the Susceptibility of Hindbrain Lineages to Medulloblastoma. Dev Cell. 2020;54(4):455-470.e5. doi:10.1016/j.devcel.2020.05.027
2. Phoenix TN, Patmore DM, Boop S, et al. Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype. Cancer Cell. 2016;29(4):508-522. doi:10.1016/j.ccell.2016.03.002
3. Gilbertson RJ and Ellison DW. The origins of medulloblastoma subtypes. Annu Rev Pathol. 3:341-65, 2008.
4. Northcott PA et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 12:818-34, 2012.
5. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468:1095-9, 2010.