Chromosomal instability drives metastasis through a cytosolic DNA response

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 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. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumor cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Cellular Stress Associated with Aneuploidy

“…Interestingly, aneuploidy in cancer cells was found to correlate with a reduced number of infiltrating cytotoxic T cells and an increased number of M2 (immune suppressive) macrophages (Davoli et al, 2017). A new study suggested that chromosomally unstable aneuploid cancer cells, though activating STING, suppressed the downstream canonical NF-κB or IFN signaling (Bakhoum et al, 2018). Instead, these cells upregulated the non-canonical NF-κB pathway, thereby engaging immune mimicry and promoting metastasis.…”

Cell-Free eccDNAs: A New Type of Nucleic Acid Component for Liquid Biopsy?

“…However, it is likely that, similar to the linear cfDNA, eccDNAs may be released by cell secretion, apoptosis (22), necrosis, cell lysis and rupture of micronuclei in either normal or diseased tissues (37), as well as from direct lysis of the circulating cells (Figure 2). A recent study showed that chromosome instability from errors during chromosome segregation may create micronuclei whose rupture released DNA into cytosol (cytosolic DNA) and activated cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway to drive their metastasis (57). eccDNAs may also be a component of these functional cytosolic DNA and actively released by tumor or diseased cells into the cytoplasm and extracellular matrix to influence the cells themselves, cells nearby and distant cells as well.…”

“…Although smaller eccDNAs (spcDNAs and microDNAs) are associated with chromosome instability, there is no direct evidence showing regulatory role of the eccDNAs. As exDNAs promote tumor cell invasion and migration and the DNase I removal of circulating exDNAs suppresses tumor metastasis (55–57), it is reasonable to hypothesize that eccDNAs may be a part of exDNAs and directly participate in regulating tumor cell invasion and metastasis. Further, circle RNAs have been identified as important regulatory molecules (59).…”

CINSARC signature as a prognostic marker for clinical outcome in sarcomas and beyond

“…This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling, which in turn co-opt chronic activation of innate immune pathways to spread to distant organs. 25 The prognostic value of CINSARC is thus supported mechanistically by (1) the pathway enrichment of the gene set restricted to mitosis and chromosome integrity and (2) the driver role of chromosomal instability in metastatic spread. Moreover, it is now clear that metastatic competence is afforded by chromosome complexity in other cancers.…”