Haston, Scott; (2019) Investigation of the Tumour Promoting Effects of Cellular Senescence During Pituitary and Lung Tumourigenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis involves understanding the role that cellular senescence plays during the early stages of adamantinomatous craniopharyngioma (ACP) and non-small cell lung cancer (NSCLC) tumourigenesis using genetically engineered mouse models. The host laboratory has previously shown that when pituitary stem cells are targeted with oncogenic β-catenin, they form clusters of stem cells that show non-cell autonomous tumour inducing potential. Using immunohistochemical and transcriptomic approaches, here I show that cluster cells are molecularly analogous in mouse and human ACP and share a signature of senescence with concomitant activation of the senescence associated secretory phenotype (SASP). I reveal that the tumour-inducing potential of the cluster cells requires a robust SASP. This is evidenced by targeting pituitary stem cells of aged mice (older than 6 months) with oncogenic β -catenin, which results in reduced SASP and decreased tumourigenesis. This suggests that a robust SASP is the likely driver of paracrine tumourigenesis in the pituitary. Further to this, the role of activated MAPK signalling during pituitary development was explored by driving the expression of oncogenic Kras (KrasG12D) and Braf (BrafV600E) in either pituitary progenitors or postnatal adult pituitary stem cells. By demonstrating a cell-autonomous expansion of the embryonic pituitary stem cells compartment with impaired differentiation potential, this study provided insight into the pathogenesis of another pituitary tumour, papillary craniopharyngioma. Finally, during oncogenic Kras-driven (KrasG12D) NSCLC progression in mice, it is observed that the adenoma phase of the tumour does not show a high level of senescence, however senescent cells are found outside and in association with the growing tumours in agreement with the concept of paracrine senescence. To study these senescent cells in vivo a new genetically engineered mouse model (p16FDR) was developed which allows for their visualisation, pharmacogenetic ablation and lineage tracing. Ablation of these senescent cells using p16FDR mice was found to reduce tumour burden and proliferation significantly. Together, these data suggest that senescence can have paracrine pro-tumourigenic properties and their therapeutic ablation may be clinically beneficial.

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