Non-cell-autonomous cancer progression from chromosomal instability

Jun Li, Melissa J. Hubisz, Ethan M. Earlie, Mercedes A. Duran, Christy Hong, Austin A. Varela, Emanuele Lettera, Matthew Deyell, Bernardo Tavora, Jonathan J. Havel, Su M. Phyu, Amit Dipak Amin, Karolina Budre, Erina Kamiya, Julie-Ann Cavallo, Christopher Garris, Simon Powell, Jorge S. Reis-Filho, Hannah Wen, Sarah Bettigole, Atif J. Khan, Benjamin Izar, Eileen E. Parkes, Ashley M. Laughney () and Samuel F. Bakhoum ()
Additional contact information
Jun Li: Memorial Sloan Kettering Cancer Center
Melissa J. Hubisz: Weill Cornell Medicine
Ethan M. Earlie: Weill Cornell Medicine
Mercedes A. Duran: Memorial Sloan Kettering Cancer Center
Christy Hong: Memorial Sloan Kettering Cancer Center
Austin A. Varela: Weill Cornell Medicine
Emanuele Lettera: Memorial Sloan Kettering Cancer Center
Matthew Deyell: Weill Cornell Medicine
Bernardo Tavora: Volastra Therapeutics Inc.
Jonathan J. Havel: Volastra Therapeutics Inc.
Su M. Phyu: University of Oxford
Amit Dipak Amin: Columbia Center for Translational Immunology
Karolina Budre: Weill Cornell Medicine
Erina Kamiya: Weill Cornell Medicine
Julie-Ann Cavallo: Memorial Sloan Kettering Cancer Center
Christopher Garris: Harvard Medical School
Simon Powell: Memorial Sloan Kettering Cancer Center
Jorge S. Reis-Filho: Memorial Sloan Kettering Cancer Center
Hannah Wen: Memorial Sloan Kettering Cancer Center
Sarah Bettigole: Volastra Therapeutics Inc.
Atif J. Khan: Memorial Sloan Kettering Cancer Center
Benjamin Izar: Columbia Center for Translational Immunology
Eileen E. Parkes: University of Oxford
Ashley M. Laughney: Weill Cornell Medicine
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center

Nature, 2023, vol. 620, issue 7976, 1080-1088

Abstract: Abstract Chromosomal instability (CIN) is a driver of cancer metastasis1–4, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06464-z

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