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

• DOI: 10.1016/j.devcel.2020.01.034
• Publication Date: 2020-02-24T22:21:32Z
• Authors: Anand Vasudevan; Prasamit S. Baruah; Joan C. Smith; Zihua Wang; Nicole M. Sayles; Peter Andrews; Jude Kendall; Justin Leu; Narendra Kumar Ch...; Dan Levy; Michael Wigler; Zuzana Storchová; Jason M. Sheltzer
• Keywords: Male; 0303 health sciences; Epithelial-Mesenchymal Transition; Membrane Proteins; Mice, Nude; Apoptosis; Aneuploidy; Nucleotidyltransferases; Xenograft Model Antitumor Assays; 3. Good health; Mice; 03 medical and health sciences; Cell Movement; Chromosomal Instability; Colonic Neoplasms; Tumor Cells, Cultured; Animals; Chromosomes, Human, Pair 5; Humans; Female; Neoplasm Invasiveness; Cell Proliferation

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.