Apps, John Richard; (2018) Molecular characterisation of childhood craniopharyngioma and identification and testing of novel drug targets. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

BACKGROUND: Adamantinomatous Craniopharyngiomas (ACPs) are clinically challenging sellar region tumours, known to be characterised by mutations in CTNNB1. ACPs are often histologically complex, with different morphological cell types and surrounded by a florid glial reaction. Murine models have been generated through activating β-catenin and support a critical role for nucleo-cytoplasmic accumulating β-catenin cell clusters (‘clusters’) in driving tumorigenesis. AIMS: To phenotype in detail the 3D growth patterns of human and murine ACP; To characterise the genomic and transcriptomic landscape of human and murine ACP, including of clusters; To characterise therapeutically targetable molecular pathways and perform pre-clinical therapeutic trials. METHODS: Human ACP samples underwent micro-focus-CT scanning, whole genome sequencing, targeted next generation sequencing and RNA sequencing, both with, and without, laser capture microdissection. The growth dynamics of murine ACP was characterised by serial MRI and a cohort of murine ACPs, at various stages, underwent RNA and exome sequencing. A pre-clinical murine trial using a Sonic Hedgehog (SHH) pathway inhibitor was performed. RESULTS: CTNNB1 mutationsin human ACP were confirmed as clonal within tumour epithelia. Gene expression signatures corresponding to tumour epithelia, reactive glia and immune infiltrate were derived and novel ACP genes were identified (e.g. BCL11B). A relationship between human and murine ACPs with the developing tooth was also established, in particular the similarity of clusters to the enamel knot. Further molecular dissection identified a complex interplay between tumour cell compartments demonstrating a role for paracrine signalling. Inhibition of the SHH pathway in the pre-clinical murine trial resulted in a decrease in median survival from 33 weeks to 11.9 weeks (p=0.048). A signature of inflammasome activation in ACP was also identified in solid and cystic components of ACP. CONCLUSIONS: ACPs have clonal mutations in CTNNB1 and exhibit complex signalling interplay between different cell compartments. Expression analysis reveals a new molecular paradigm for understanding ACP tumorigenesis as an aberrant copycat of natural tooth development, with inflammation driven by activation of inflammasomes. Caution is recommended in the use of SHH pathway inhibitors in patients with ACP.

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