Divergent differentiation in brain tumours

Background:
Brain tumours are the commonest cause of cancer-related death in children and young adults, and even amongst the survivors, there is a high-risk of disability and morbidity. These long-term consequences are, at least in part, due to the impact of the aggressive treatments often required to cure the tumours. Therefore, these tumours pose a substantial clinical challenge.

A recurrent feature of many tumour types, particularly those within the brain, is that they exhibit variable differentiation down multiple cellular lineages, sometimes appropriate to the tissue of origin (e.g., glial and neuronal differentiation in gangliogliomas) or in others, not appropriate to the local tissue (i.e., heterologous differentiation, e.g., muscle differentiation in the brain tumour, medulloblastoma (medulloblastoma with myoblastic differentiation)). Other tumours fail to differentiate towards any mature cell type or do so while maintaining an undifferentiated component. The factors that regulate this variable pattern of differentiation are poorly understood, particularly in the examples where the tumours show heterologous differentiation[2–4].

We have investigated two exemplars of these phenomena. The first are epilepsy associated tumours which show differentiation along tissue-appropriate lineages in a pattern that is predicted by their epigenetic profile and underlying driving mutation[4]. The second are a subtype of an embryonal tumour (medulloblastoma) that in some examples show differentiation towards muscle, melanocytes, or other mature tissue types. Using these as exemplars, we have obtained preliminary data describing the molecular factors that characterise these tumour types ([4] and unpublished data).

Aims/Objectives:
The aim of this project is to understand what events occur during tumorigenesis that lead to such diverse patterns of differentiation, particularly in those tumours that show heterologous differentiation.

Methods:
The student will analyse existing transcriptional and epigenetic data from well characterised cohorts of these tumours to identify markers of cellular identity, transcription factors and signalling molecules[1] to identify factors regulating cellular differentiation. The functional role of candidate molecules will be tested in primary cultures of the relevant cell types using approaches already established in the group ([1] and unpublished data). Finally, candidates pathways derived from these archetypal tumours will be investigated in a larger cohort of childhood brain tumours to determine to what extent the processes are shared in other tumours showing less overt divergent differentiation. The expertise required to undertake the data analysis is covered within the supervisors’ groups [1-4].

References:
1. Li Y, Scerif, F., Picker, S.R., Stone, T.J., … Hargrave D, Guillemot F, Paine S, Yasin SA, Jacques TS (2021) Identifying cellular signalling molecules in developmental disorders of the brain: Evidence from focal cortical dysplasia and tuberous sclerosis. Neuropath Appl Neuro. doi: 10.1111/nan.12715.
2. Pickles, J.C., Fairchild, A.R, Stone, T.J., …, Hargrave D, Chalker J, Jacques TS (2020) DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study. The Lancet Child and Adolescent Health 4:121–130.
3. Pickles JC, Stone TJ, Jacques TS (2020) Methylation‐based algorithms for diagnosis: experience from neuro‐oncology. Journal of Pathology 20:608–608.
4. Stone TJ, …, Hargrave D, Ham J, Jacques TS (2018) Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours. Acta Neuropathologica 135:115–129.