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

Abstract

Chromosomal instability (CIN), an increased rate of changes in chromosome structure and number, is observed in most human carcinomas. Drosophila epithelial tumour models have been instrumental in demonstrating that, beyond the generation of genomic copy number heterogeneity, 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. This unique transcriptional program shows that most cellular responses to aneuploidy and senescence, such as cell cycle arrest, autophagy induction, activation of the actin cytoskeleton, and upregulation of genes involved in secretion, are regulated at the transcriptional level. In addition to the secreted proteins mediating tumour growth, metastasis, and malignancy, we unravel a role of cytokine Upd1 in driving the death of those cells that comprise the nearby tumour microenvironment through activation of the JAK/STAT pathway and induction of autophagy. We also demonstrate a pro-survival role of the Hippo-Yorkie pathway in tumour 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.