Non-cell-autonomous cancer progression from chromosomal instability

• Published in: Nature (London) Vol. 620; no. 7976; pp. 1080 - 1088
• Main Authors: Li, Jun, Hubisz, Melissa J., Earlie, Ethan M., Duran, Mercedes A., Hong, Christy, Varela, Austin A., Lettera, Emanuele, Deyell, Matthew, Tavora, Bernardo, Havel, Jonathan J., Phyu, Su M., Amin, Amit Dipak, Budre, Karolina, Kamiya, Erina, Cavallo, Julie-Ann, Garris, Christopher, Powell, Simon, Reis-Filho, Jorge S., Wen, Hannah, Bettigole, Sarah, Khan, Atif J., Izar, Benjamin, Parkes, Eileen E., Laughney, Ashley M., Bakhoum, Samuel F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.08.2023; Nature Publishing Group
• Subjects: 13/21; 13/31; 13/51; 14; 14/1; 14/63; 38; 38/91; 631/250/256/2515; 631/67/322; 631/67/327; 631/67/580; 631/80/103; Benchmarking; Breast cancer; Cell Communication; Cell interactions; Cells; Cellular stress response; Chromosomal Instability; Chromosomes; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Contact tracing; CRISPR; Disease Progression; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Genomic instability; Humanities and Social Sciences; Humans; Immune system; Interferon Type I - immunology; Ligands; Lymphocytes; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - immunology; Melanoma - pathology; Metastases; Metastasis; Micronuclei; multidisciplinary; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Science; Science (multidisciplinary); Signal Transduction; Tachyphylaxis; Transcriptomics; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - pathology; Tumor Microenvironment; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06464-z

Chromosomal instability (CIN) is a driver of cancer metastasis 1 – 4 , yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing—a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell–cell interactions from single-cell transcriptomic data—we show that CIN-induced chronic activation of the cGAS–STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation. Chromosomal instability in cancer is linked to endoplasmic reticulum stress signalling, immune suppression and metastasis, which is mediated by the cGAS–STING pathway, suppression of which can reduce metastasis.