Chromosomal instability-induced senescence potentiates cell non-autonomous tumourigenic effects

Chromosomal instability (CIN), a higher propensity for loss or gain of whole chromosomes, is a hallmark of cancer and is associated with poor prognosis and drug resistance in multiple types of cancers. CIN often generates aneuploid, including polyploid, cells which contain abnormal number of chromosomes. Despite the prevalence of aneuploidy in tumours, the cell fates following different degrees of chromosome mis-segregation and aneuploidy and how aneuploidy contributes to tumourigenesis remain unclear. Here in this study, we generated relatively mild and severe forms of random aneuploidy in chromosomally stable cells using nocodazole (a microtubule depolymerisation drug) and reversine (spindle assembly checkpoint (SAC) kinase Mps1 inhibitor). We found that severe forms of aneuploid, including polyploid cells, led to senescence, which is classically defined as an irreversible cell cycle arrest. Conversely, mild forms of aneuploidy continued proliferation. Additionally, aneuploidy induced by genetic intervention mechanisms through knockdown of SAC component BUB1 and cohesion subunit SMC1A also culminated in senescence, further substantiating the notion that aneuploidy is sufficient to trigger senescence. These senescent cells were observed to exhibit persistent DNA damage and robust p53 activation. We further found that depletion of p53 significantly reduced the number of senescent cells with concomitant increase in cells undergoing DNA synthesis, suggesting the senescence growth arrest is p53-dependent. Importantly, further characterisation revealed that these aneuploidy-induced senescent cells acquired the senescence-associated secretory phenotype (SASP) which is characterised by increased secretion of a variety of pro-inflammatory factors including cytokines, chemokines, growth factors and matrix remodelling factors and so on. Subsequent phenotypic analysis demonstrated that these SASP factors conferred paracrine pro-tumourigenic effects such as cell migration, invasion and angiogenesis both in vitro and in vivo. Finally, we observed a correlation between high levels of aneuploidy and senescence at the invasive front in invasive ductal breast carcinomas. Collectively, our findings demonstrate functional non-equivalence of discernable random aneuploidies on tumourigenesis and suggest a cell non-autonomous mechanism by which aneuploidy-induced senescence and SASP can affect the tumour microenvironment to promote tumour progression.Doctor of Philosoph