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bioRxiv · 10.1101/2020.07.11.196790

STING Promotes Breast Cancer Cell Survival by an Inflammatory-Independent Nuclear Pathway Enhancing the DNA Damage Response

Laura Cheradame·Ida C Guerrera·Julie Gaston·Alain Schmitt·Vincent Jung·Marion Pouillard·Nina Radosevic-Robin·Mauro Modesti·Jean-Gabriel Judde·Stefano Cairo·Vincent Goffin
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Abstract

STING (Stimulator of Interferon Genes) is a well-known endoplasmic reticulum-anchored adaptor of the innate immunity that triggers the expression of inflammatory cytokines in response to pathogen infection. In cancer cells, this pro-inflammatory pathway can be activated by genomic DNA damage potentiating antitumor immune responses. Here we report that STING promotes cancer cell survival and resistance to genotoxic treatment in a cell-autonomous manner. Mechanistically, we show that STING partly localizes at the inner nuclear membrane in various breast cancer cell lines and clinical tumor samples, and interacts with several proteins of the DNA damage response (DDR). STING overexpression enhances the amount of chromatin-bound DNA-dependent Protein Kinase (DNA-PK) complex, while STING silencing impairs DDR foci formation and DNA repair efficacy. Importantly, this function of STING is independent of its canonical pro-inflammatory pathway. This study highlights a previously unappreciated cell-autonomous tumor-promoting mechanism of STING that opposes its well-documented role in tumor immunosurveillance. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/196790v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@ba73f5org.highwire.dtl.DTLVardef@11319ccorg.highwire.dtl.DTLVardef@102bb4corg.highwire.dtl.DTLVardef@56b8a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Laura Cheradame, Ida C Guerrera, Julie Gaston, Alain Schmitt, Vincent Jung, Marion Pouillard, Nina Radosevic-Robin, Mauro Modesti, Jean-Gabriel Judde, Stefano Cairo, Vincent Goffin. 2020-07-12. STING Promotes Breast Cancer Cell Survival by an Inflammatory-Independent Nuclear Pathway Enhancing the DNA Damage Response. https://doi.org/10.1101/2020.07.11.196790

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