A tumour-host feed-forward loop contributes to the growth of chromosomal instability-induced tumours

Chromosomal instability (CIN), characterized by frequent changes in chromosome number and structure, is common in human carcinomas and often leads to aneuploidy, an unbalanced number of chromosomes. Drosophila has been instrumental in demonstrating that CIN can promote tumour growth and malignancy through aneuploidy-induced senescence, a state marked by cell-cycle arrest and high secretory activity. Despite extensive chromosomal heterogeneity, we show that these cells share a distinct transcriptional programme, with most responses to aneuploidy and senescence regulated at the transcriptional level. We unravel a pro-survival function of the Hippo-Yorkie signalling pathway in aneuploidy-induced senescent cells and present evidence that nearly 10% of the most upregulated genes encode secreted proteins of the senescence-associated secretory phenotype. Five of these proteins act additively, locally or systemically, to block proliferation and induce cell death in neighbouring tissues. This non-autonomous cell death feeds back to the tumour to enhance its growth, resembling super-competition and providing insight into tumour-host interactions relevant to human cancer.