Journal Article

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

Pieters, Wietske, Hong, Christy, Schubert, Michael, de Bruyn, Marco, Tijhuis, Andréa E., Ruiz, Lorena Andrade, Wardenaar, René, van der Vegt, Bert, van der Sluis, Tineke, van Vugt, Marcel A. T. M., Chen, Mengting, Spierings, Diana C. J., Foijer, Floris, Requesens, Marta, van den Brink, Anouk, Roorda, Maurits, Bakker, Petra L.

2022

Overview

Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis 1 . CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING 2 , 3 . These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer 4 , and, although they have been implicated in metastasis 5 , it is not known why loss-of-function mutations do not arise in primary tumours 4 . 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. The survival of cells with chromosomal instability (CIN) depends on the cGAS–STING pathway, in which IL-6 and its receptor have a key role; this vulnerability can be exploited to treat tumours that display CIN.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/109 / 13/21 / 13/95 / 14 / 14/63 / 45 / 45/23 / 45/91 / 631/67/1347 / 631/80/86/2366 / 64/60 / 96 / 96/31 / Antibodies, Monoclonal, Humanized - pharmacology / Apoptosis / Breast cancer / Cancer / Cancer therapies / Cell Survival - drug effects / Chromosomal Instability - genetics / CRISPR / Cytoplasm / Deactivation / Drug Repositioning / Genomic instability / Humanities and Social Sciences / Humans / Immunosurveillance / Inactivation / Inflammation / Interleukin 6 / Interleukin-6 - antagonists & inhibitors / Interleukin-6 - metabolism / Localization / Membrane Proteins - genetics / Membrane Proteins - metabolism / Metabolism / Metastases / Micronuclei / Monoclonal antibodies / multidisciplinary / Mutation / NF-kappa B - metabolism / NF-κB protein / Nucleotidyltransferases - genetics / Nucleotidyltransferases - metabolism / Phosphorylation / Receptors, Interleukin-6 - antagonists & inhibitors / Receptors, Interleukin-6 - metabolism / Science / Science (multidisciplinary) / Signal transduction / Signal Transduction - drug effects / Signaling / Stat3 protein / STAT3 Transcription Factor - metabolism / Suppressors / Survival / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Tumors