Chromosomal Instability Drives Metastasis Independent of Aneuploidy

Chromosomal instability (CIN), which results from ongoing chromosome segregation errors in mitosis, is associated with metastasis. However, it is not clear if CIN drives metastatic progression. Bakhoum, Ngo, and colleagues sought to determine the role of CIN in metastasis by overexpressing KIF2B or MCAK to destabilize microtubule attachments to chromosome kinetochores, thereby suppressing CIN, an approach that allows experimental examination of CIN independent of aneuploidy. CIN was increased in metastases compared with primary tumors in patients with multiple tumor types. Overexpressing KIF2B or MCAK in breast cancer cells suppressed CIN, resulting in stable aneuploid cells with an unchanged proliferative capacity. These cells were injected into the left cardiac ventricles of athymic mice to facilitate systemic dissemination using a bioluminescence reporter to track metastatic colonization. CIN-high cells induced rapid metastatic disease, whereas CIN-low cells resulted in a lower metastatic burden and extended survival, suggesting that CIN drives metastasis. Similarly, in a metastasis model in which tumor cells were orthotopically injected in mammary fat pads followed by surgical excision of the primary tumor, suppressing CIN reduced metastasis and extended survival without affecting primary tumor growth. RNA sequencing of CIN-low and CIN-high breast cancer cells revealed that CIN enriched for mesenchymal genes including those involved in epithelial-to-mesenchymal transition (EMT) and metastasis, and upregulation of inflammation-associated genes. In CIN-high cells, chromosome segregation errors increased the number of micronuclei, which ruptured, leading to increased cytosolic DNA, activation of the cytosolic DNA-sensing cGAS–STING pathway, and activation of downstream noncanonical NF-κB signaling to promote metastasis and STING-mediated upregulation of EMT and inflammatory genes. In addition to demonstrating that CIN drives metastatic progression, these findings link activation of the cytosolic DNA sensing cGAS–STING pathway to metastatic progression.

Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 2018;553:467–72.

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