Shroff, Aditya Shishir; (2023) Deciphering the role of mutant IDH in gliomas via development of novel in vivo models. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Gliomas are among the most lethal human neoplasms. Patient tumor studies have led to advancements in the molecular classification of adult diffuse low-grade gliomas (LGG) associated with mutations in the isocitrate dehydrogenase 1 (IDH1) gene. However, translating these insights into biology for therapeutic purposes has lagged behind. This is in part due to a lack of precise autochthonous preclinical models that faithfully recapitulate the genetics and biology of disease progression, whilst allowing the study of intrinsic disease heterogeneity concurrently with the tumor microenvironment (TME) interactions. In this thesis, we employed postnatal brain electroporation to develop a slowly progressing somatic IDH1 mutant (IDH1R132H; IDHmut) murine model. We show that IDH1 mutant, combined with loss of the tumour suppressor protein 53 (Tp53) and α-thalassemia/mental retardation syndrome X-linked (Atrx) genes, is sufficient to drive formation of diffuse gliomas with resulting tumours recapitulating the histopathology and molecular hallmarks of IDHmut-astrocytomas (IDH-A) patient tumours. Multi-omic based molecular characterisation and integrative data analyses led to the identification of novel cell intrinsic as well as extrinsic molecular signatures, characterised by epigenetic modifications, disruption of the neuro-glioma axis and altered composition of the TME features, respectively. Further murine modeling identified a previously unrecognized subgroup of IDH-A patients accompanied by distinct somatic copy number alterations and an enriched immune-TME. The murine signatures link with epigenetic regulator Ezh2, correlated it to progression and was verified in a new progressive dual-oncogene-driven IDH-A model. Collectively, our results provide insights into IDH-A pathogenesis, intrinsic tumor characteristic associated with TME heterogeneity and uncovering an opportunity for patient stratification with prognostic value.

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