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
