Abstract CN01-02: Chromosomal instability as a driver of tumor metastasis

Abstract

Abstract 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 rupture-prone micronuclei that expose their DNA content to 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. Citation Format: Samuel F. Bakhoum. Chromosomal instability as a driver of tumor metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN01-02.