Uncovering new mechanisms for aneuploidy tolerance in cancer cells

Aneuploidy, an imbalanced number of chromosomes or chromosome-arms, is the most common genetic aberration in cancer. However, aneuploidy induces several cellular stresses, including replication, mitotic, metabolic and proteotoxic. In non-transformed somatic cells, these stresses are detrimental and often lead to cell cycle arrest and cell death. Therefore, for aneuploidy to become beneficial, tolerance mechanisms that enable cancer cells to cope with aneuploidy-induced cellular stresses must come into play.

To systematically dissect the cellular mechanisms that facilitate aneuploidy tolerance, we analyzed data from human tumors, cancer cell lines and non-transformed cells. First, we identified genes whose expression and essentiality were strongly correlated with aneuploidy. To further focus on aneuploidy tolerance, we compared expression (by RNAseq) and essentiality (by a genome-wide CRISPR screen) between fast- and slow-cycling cells exposed to an aneuploidy-inducing drug. Additionally, we identified aneuploidy-dependent associations between gene expression and doubling time, as well as aneuploidy-specific drug response across pharmacological screens. Our analysis identified 55 genes associated with aneuploidy tolerance with high confidence. This list was enriched for several pathways, namely ribosome biogenesis and translation, DNA repair, replication stress and the p53 pathway.

A top hit from this analysis was DDX27, an RNA helicase with an unclear cellular function. Using several isogenic aneuploid systems of both transformed and non-transformed backgrounds, we validated that DDX27 overexpression was a general feature of aneuploid cells. Our work links DDX27 to the above-mentioned aneuploidy-associated cellular pathways, shedding light on its cellular functions and on its role in aneuploidy tolerance.