cGAS–STING drives the IL-6-dependent survival of chromosomally instable cancers

Christy Hong, Michael Schubert, Andréa E. Tijhuis, Marta Requesens, Maurits Roorda, Anouk Brink, Lorena Andrade Ruiz, Petra L. Bakker, Tineke Sluis, Wietske Pieters, Mengting Chen, René Wardenaar, Bert Vegt, Diana C. J. Spierings, Marco Bruyn (), Marcel A. T. M. Vugt () and Floris Foijer ()
Additional contact information
Christy Hong: University of Groningen, University Medical Center Groningen
Michael Schubert: University of Groningen, University Medical Center Groningen
Andréa E. Tijhuis: University of Groningen, University Medical Center Groningen
Marta Requesens: University of Groningen, University Medical Center Groningen
Maurits Roorda: University of Groningen, University Medical Center Groningen
Anouk Brink: University of Groningen, University Medical Center Groningen
Lorena Andrade Ruiz: University of Groningen, University Medical Center Groningen
Petra L. Bakker: University of Groningen, University Medical Center Groningen
Tineke Sluis: University of Groningen, University Medical Center Groningen
Wietske Pieters: Netherlands Cancer Institute
Mengting Chen: University of Groningen, University Medical Center Groningen
René Wardenaar: University of Groningen, University Medical Center Groningen
Bert Vegt: University of Groningen, University Medical Center Groningen
Diana C. J. Spierings: University of Groningen, University Medical Center Groningen
Marco Bruyn: University of Groningen, University Medical Center Groningen
Marcel A. T. M. Vugt: University of Groningen, University Medical Center Groningen
Floris Foijer: University of Groningen, University Medical Center Groningen

Nature, 2022, vol. 607, issue 7918, 366-373

Abstract: Abstract Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis1. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING2,3. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer4, and, although they have been implicated in metastasis5, it is not known why loss-of-function mutations do not arise in primary tumours4. Here we show that inactivation of cGAS–STING signalling selectively impairs the survival of triple-negative breast cancer cells that display CIN. CIN triggers IL-6–STAT3-mediated signalling, which depends on the cGAS–STING pathway and the non-canonical NF-κB pathway. Blockade of IL-6 signalling by tocilizumab, a clinically used drug that targets the IL-6 receptor (IL-6R), selectively impairs the growth of cultured triple-negative breast cancer cells that exhibit CIN. Moreover, outgrowth of chromosomally instable tumours is significantly delayed compared with tumours that do not display CIN. Notably, this targetable vulnerability is conserved across cancer types that express high levels of IL-6 and/or IL-6R in vitro and in vivo. Together, our work demonstrates pro-tumorigenic traits of cGAS–STING signalling and explains why the cGAS–STING pathway is rarely inactivated in primary tumours. Repurposing tocilizumab could be a strategy to treat cancers with CIN that overexpress IL-6R.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04847-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:607:y:2022:i:7918:d:10.1038_s41586-022-04847-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04847-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().