Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer

High levels of cancer aneuploidy are frequently associated with poor prognosis. To examine the relationship between aneuploidy and cancer progression, we analyzed a series of congenic cell lines that harbor single extra chromosomes. We found that across 13 different trisomic cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, we discovered that chromosomal instability activates cGAS/STING signaling but strongly suppresses invasiveness. By analyzing patient copy-number data, we demonstrate that specific aneuploidies are associated with distinct outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different aneuploidies can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, thereby linking genomic plasticity, phenotypic plasticity, and metastasis. •A trisomy increases metastatic behavior in colon cancer cells by inducing a partial EMT•Chromosomal instability activates cGAS/STING signaling but suppresses invasiveness•Whole-chromosome aneuploidies show strong correlations with prognosis across cancers Tumors often display chromosome copy-number changes that have poorly understood effects on cancer physiology. Vasudevan et al. demonstrate that different aneuploidies have distinct effects on invasive behavior and that specific aneuploidies are tightly correlated with clinical outcomes. They also reveal that chromosomal instability can profoundly suppress metastatic dissemination.