Gonzalez Meljem, JM; (2017) The role of cytokine signalling, cellular senescence and its secretory phenotype in normal pituitary development and tumourigenesis. Doctoral thesis , UCL (University College London).

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Abstract

Oncogene-induced senescence (OIS) is classically described as a potent antitumourigenic barrier that restrains the proliferation of pre-malignant cells. Senescent cells can also promote immune clearance by secreting a plethora of chemokines and inflammatory factors, collectively known as the Senescence-Associated Secretory Phenotype (SASP). However, the SASP can also promote tumourigenesis paracrinally. In this study, OIS and the SASP were studied in mouse models for adamantinomatous craniopharyngioma (ACP), which express oncogenic β-catenin in pituitary progenitors/stem cells. Surprisingly, oncogenic β-catenin-targeted cells did not give rise to the tumour mass in the majority of cases and stopped dividing after a short burst of proliferation to form β-catenin-accumulating cell clusters. Here it is demonstrated that β-catenin clusters undergo OIS as determined by a lack of proliferation markers, activation of the p53/p21 and p16/Rb pathways, induction of the DNA damage response (DDR) and activation of the NF-κB pathway. Additionally, unbiased mRNA expression analysis shows enrichment of OIS and SASP genes in β-catenin clusters, while SASP gene expression is corroborated by qRT-PCR and ELISA assays. Of translational significance, these results are recapitulated in the β- catenin clusters of human ACP. Furthermore, evidence is presented indicating that the paracrine signals secreted by the β-catenin clusters are involved in non-cell autonomous tumourigenesis through modification of their microenvironment and the recruitment of endothelial progenitors displaying aberrant SOX9 expression. A genetic strategy demonstrated that induction of OIS and the SASP in the clusters is p53-independent, but that p53 is required to prevent a full bias for cell-autonomous tumourigenesis. Finally, a mouse line that also develops β-catenin clusters, albeit with a dampened SASP is described. These clusters do not appear to modify their microenvironment and tumours do not develop. Together, the mouse and human data suggest that senescence and SASP are likely to modify the tumour microenvironment resulting in cell transformation, tumour growth and survival.

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