Non-cell-autonomous cancer progression from chromosomal instability Journal Article


Authors: Li, J.; Hubisz, M. J.; Earlie, E. M.; Duran, M. A.; Hong, C.; Varela, A. A.; Lettera, E.; Deyell, M.; Tavora, B.; Havel, J. J.; Phyu, S. M.; Amin, A. D.; Budre, K.; Kamiya, E.; Cavallo, J. A.; Garris, C.; Powell, S.; Reis-Filho, J. S.; Wen, H.; Bettigole, S.; Khan, A. J.; Izar, B.; Parkes, E. E.; Laughney, A. M.; Bakhoum, S. F.
Article Title: Non-cell-autonomous cancer progression from chromosomal instability
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. © 2023, The Author(s).
Keywords: genetics; melanoma; immune system; benchmarking; chromosomal instability; tumor; cell communication; nucleotidyltransferase; inhibition; instability; cell; tumor microenvironment; nucleotidyltransferases; stress analysis; cancer; humans; human
Journal Title: Nature
Volume: 620
Issue: 7976
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2023-08-31
Start Page: 1080
End Page: 1088
Language: English
DOI: 10.1038/s41586-023-06464-z
PUBMED: 37612508
PROVIDER: scopus
PMCID: PMC10468402
DOI/URL:
Notes: Article -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Simon Nicholas Powell
    331 Powell
  2. Hannah Yong Wen
    301 Wen
  3. Samuel F Bakhoum
    81 Bakhoum
  4. Atif Jalees Khan
    153 Khan
  5. Mercedes A Duran
    12 Duran
  6. Jun Li
    10 Li
  7. Christy Hong
    3 Hong