Garcia Diaz, Claudia; (2022) Novel de novo Glioblastoma mouse models reveal differences in the biology of the tumour bulk and invasive margin. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glioblastoma (GBM) is a devastating primary brain tumour with an average survival of less than two years, despite standard-of-care treatment. This dismal prognosis is largely due to the highly heterogeneous and diffusive nature of GBM leading to disease recurrence. Indeed, tumours inevitably recur from invasive cells that had eluded initial surgical resection and successive chemoand radiotherapeutic interventions. Bulk studies have shown that GBM tumours are molecularly and cellularly diverse; however, the cellular composition and the impact of the mutational burden on the biology of the infiltrative margin remains understudied. In this work, we established three de novo syngeneic mouse models – by transforming endogenous neural stem cells with subtype-specific driver mutations – that recapitulate the cellular and histopathological make-up of GBM. By comparing the transcriptome of individual tumour cells isolated from the bulk and infiltrative margin, we found that, irrespectively of underlying genetics, tumour cells converge onto developmental- and injury-like glial states. Furthermore, we show that tumour region is a major determinant of cell fate choice: the infiltrative margin favours an astrocyte-like fate, whereas the tumour bulk promotes a dormant injuryneural progenitor-like (iNPC-like) fate. To track the dormant populations, we introduced a label-retention reporter into our mouse models and confirmed an enrichment of iNPC-like fate at the bulk. We further show that iNPC-like enrichment is correlated with a stronger immune infiltration at the bulk, relative to the infiltrative margin, and that iNPC-like tumour cells are located near T cell niches. Finally, through loss-of function studies, we identify that acquisition of this dormant phenotype is interferon-mediated. Taken together, these results indicate that tumour region primarily dictates cell fate, and, thus, therapeutic strategies devised from studying the bulk may not address the distinct biology of the infiltrative tumour populations which will eventually constitute the residual disease.

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