Journal article
Non-cell-autonomous cancer progression from chromosomal instability
- Abstract:
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Chromosomal instability (CIN) is a hallmark of human cancer that is associated with metastasis and immune evasion1-4. While CIN is a cancer cell-intrinsic property, the extent to which CIN depends on the immune system to drive tumor progression is unknown. Here we show that CIN-dependent chronic activation of the cGAS-STING innate immune pathway promotes cancer progression in a tumor cell non-autonomous manner. Ongoing chromosome missegregation engenders a pro-metastatic tumor microenvironment (TME) that is markedly enriched for immune-suppressive macrophages, a granulocytic infiltrate, and dysfunctional T cells. Using ContactTracing, a newly developed, validated, and benchmarked tool to infer conditionally-dependent cell-cell interactions from single cell RNA sequence data, we identify a tumor cell-derived and STING-dependent ER-stress response as a key mediator of tumor progression. CIN-induced chronic STING activation promotes interferon-selective tachyphylaxis and rewires signaling downstream of STING to promote ER-stress-dependent transcription. Suppression of CIN, depletion of cancer cell STING, or inhibition of ER-stress signaling reverses CIN-dependent effects on the TME and suppresses metastasis in immune competent, but not severely immune compromised settings. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER-stress signaling, immune suppression, and metastasis in human triple-negative breast cancer highlighting a strategy to identify and therapeutically intervene in tumors driven by CIN-induced inflammation.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 56.0MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-023-06464-z
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 620
- Issue:
- 7976
- Pages:
- 1080-1088
- Publication date:
- 2023-08-23
- Acceptance date:
- 2023-07-20
- DOI:
- EISSN:
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1476-4687
- ISSN:
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0028-0836
- Language:
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English
- Keywords:
- Pubs id:
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1560467
- Local pid:
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pubs:1560467
- Deposit date:
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2025-03-24
- ARK identifier:
Terms of use
- Copyright holder:
- Li et al.
- Copyright date:
- 2023
- Rights statement:
- Copyright © 2023, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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