The transcriptome of aneuploidy-induced senescent cells reveals interaction with the tumour microenvironment and a pro-survival role of Yorkie

Chromosomal instability (CIN), characterized by frequent changes in chromosome number and structure, is common in human carcinomas and often leads to aneuploidy. 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 program, with most responses to aneuploidy and senescence regulated at the transcriptional level. 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-autonomo*us 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. Teaser: Aneuploidy-induced senescent cells activate the pro-survival Hippo-Yorkie pathway and the SASP drives tumour host interactions