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

Chromosomal instability (CIN)—an increased rate of changes in chromosome structure and number—is observed in most human carcinomas. Drosophila has been instrumental in demonstrating that CIN can act as a source of tumour growth, metastasis, and malignancy through the production of aneuploidy-induced senescent cells. Here we unravel a distinct transcriptional program in these cells, despite their highly heterogeneous chromosome content, and show that most cellular responses to aneuploidy and senescence are regulated at the transcriptional level. The senescence-associated secretory phenotype of aneuploid cells consist of more than 40 secreted proteins. We identify four secreted proteins acting on the neighbouring TME to drive cell death, suppress growth, and block proliferation and demonstrate a pro-survival role of the Hippo-Yorkie pathway in senescent cells. Our data contribute to the identification of potential therapeutic strategies to block CIN-induced tumorigenesis by targeting senescent cells and blocking their ability to interact with the tumour microenvironment.