Non-cell-autonomous cancer progression from chromosomal instability PMID: 37612508

RQC and Longevity Regulation

2026-09-03

Non-cell-autonomous cancer progression from chromosomal instability

Nature. 2023 Aug;620(7976):1080-1088. doi: 10.1038/s41586-023-06464-z.

Jun Li ^# ¹ ² , Melissa J Hubisz ^# ³ ⁴ ⁵ ⁶ , Ethan M Earlie ^# ³ ⁴ ⁵ , Mercedes A Duran ^# ¹ ² , Christy Hong ¹ ² , Austin A Varela ³ ⁴ ⁵ , Emanuele Lettera ¹ ² , Matthew Deyell ³ ⁴ ⁵ , Bernardo Tavora ⁷ , Jonathan J Havel ⁷ , Su M Phyu ⁸ , Amit Dipak Amin ⁹ ¹⁰ , Karolina Budre ³ ⁴ ⁵ , Erina Kamiya ³ ⁴ ⁵ , Julie-Ann Cavallo ¹ ² , Christopher Garris ¹¹ ¹² , Simon Powell ² , Jorge S Reis-Filho ¹³ , Hannah Wen ¹³ , Sarah Bettigole ⁷ , Atif J Khan ² , Benjamin Izar ⁹ ¹⁰ , Eileen E Parkes ⁸ , Ashley M Laughney ^# ¹⁴ ¹⁵ ¹⁶ , Samuel F Bakhoum ^# ¹⁷ ¹⁸

Affiliations

1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3. Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
4. Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
5. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
6. Bioinformatics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA.
7. Volastra Therapeutics Inc., New York, NY, USA.
8. Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, UK.
9. Columbia Center for Translational Immunology, New York, NY, USA.
10. Division of Hematology and Oncology, Columbia University Medical Center, New York, NY, USA.
11. Department of Pathology, Harvard Medical School, Boston, MA, USA.
12. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
13. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
14. Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. [email protected].
15. Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. [email protected].
16. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. [email protected].
17. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
18. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
# Contributed equally.

Abstract

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.