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Chromosomal instability (CIN) is a hallmark of cancer and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling. Genetic suppression of CIN significantly delays metastasis even in highly aneuploid tumor models, whereas inducing continuous chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. Using single-cell RNA sequencing, we uncover a CIN-induced transcriptional switch from a proliferative and metabolically active state to a mesenchymal phenotype associated with inflammatory pathways, offering an opportunity to target chromosome segregation errors for therapeutic benefit. Our work reveals an unexpected link between CIN, cytosolic DNA sensing pathways, and metastasis. The use of an isogenic system has enabled us to dissect the role of CIN from that of aneuploidy. Importantly, while we do not discount the role of CIN in generating karyotypic heterogeneity that can serve as the substrate for natural selection, our work demonstrates that continuous chromosome missegregation is also required to replenish cytosolic DNA pools leading to chronic upregulation of inflammatory pathways. In non-transformed settings, cytosolic DNA sensing is incompatible with viability. Unlike normal cells, chromosomally unstable cells are awash with cytosolic DNA and have adapted to coexist with a chronically active cGAS-STING pathway by suppressing downstream type I interferon signaling and instead upregulating the alternative NF-κB pathway. Persistent STING activation mediates carcinogen-induced tumor formation and we now show that tumor cells co-opt this otherwise lethal program to spread to distant organs. The evolutionary benefit of the noncanonical pathway might justify the scarcity of inactivating mutations in cGAS and STING among human cancers. The emergence, and subsequent tolerance, of CIN represents an important bottleneck during tumor evolution. Our single-cell analysis revealed that CIN induces a transcriptional switch whereby cells shift from a proliferative and highly metabolic state, ideally suited for primary tumor growth, to a chromosomally unstable and mesenchymal state associated with upregulation of inflammatory pathways. These two largely mutually exclusive states likely account for the reversibility in chromosome missegregation rates seen in primary tumors and metastases, and provide an explanation for the negative effect of aneuploidy during early tumorigenesis. Interestingly, this mutual exclusivity was recently observed in a pan-cancer genomic analysis of metastatic tumors, and it leads us to suggest that CIN underlies the subset of metastases that are characterized by EMT and inflammation. By providing a mechanistic link between CIN and metastasis, our work opens new avenues to target chromosomally unstable tumors for therapeutic benefit. Citation Format: Samuel F. Bakhoum, Bryon Ngo, Ashley L. Bakhoum, Julie-Ann Cavallo, Charles J. Murphy, Peter Ly, Pragya Shah, Roshan K. Sriram, Thomas B.k. Watkins, Neil K. Taunk, Mercedes Duran, Chantal Pauli, Christine Shaw, Kalyani Chadalavada, Vinagolu K. Rajasekhar, Giulio Genovese, Subramanian Venkatesan, Nicolai J. Birkbak, Nicholas McGranahan, Mark Lundquist, Quincy LaPlant, John H. Healey, Olivier Elemento, Christine H. Chung, Nancy Y. Lee, Marcin Imielinski, Gouri Nanjangud, Dana Pe9er, Don W. Cleveland, Simon N. Powell, Jan Lammerding, Charles Swanton, Lewis C. Cantley. Chromosomal instability promotes metastasis through a cytosolic DNA response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr NG03.

Abstract NG03: Chromosomal instability promotes metastasis through a cytosolic DNA response