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STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway

Abstract

STING (Stimulator of Interferon Genes) is an endoplasmic reticulum-anchored adaptor of the innate immunity best known to trigger pro-inflammatory cytokine expression in response to pathogen infection. In cancer, this canonical pathway can be activated by intrinsic or drug-induced genomic instability, potentiating antitumor immune responses. Here we report that STING downregulation decreases cell survival and increases sensitivity to genotoxic treatment in a panel of breast cancer cell lines in a cell-autonomous manner. STING silencing impaired DNA Damage Response (53BP1) foci formation and increased DNA break accumulation. These newly identified properties were found to be independent of STING partner cGAS and of its canonical pro-inflammatory pathway. STING was shown to partially localize at the inner nuclear membrane in a variety of breast cancer cell models and clinical tumor samples. Interactomics analysis of nuclear STING identified several proteins of the DNA Damage Response, including the three proteins of the DNA-PK complex, further supporting a role of STING in the regulation of genomic stability. In breast and ovarian cancer patients that received adjuvant chemotherapy, high STING expression is associated with increased risk of relapse. In summary, this study highlights an alternative, non-canonical tumor-promoting role of STING that opposes its well-documented function in tumor immunosurveillance.

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Fig. 1: STING promotes intrinsic breast cancer cell survival and resistance to genotoxic stress.
Fig. 2: STING is a positive regulator of the DDR.
Fig. 3: STING impact on DNA integrity and cancer cell survival is independent of its canonical pro-inflammatory pathway.
Fig. 4: STING partly resides in the nucleus of breast cancer cells.
Fig. 5: STING co-localizes with the lamina in breast cancer cells.
Fig. 6: Identification of STING at the INM by electronic microscopy.
Fig. 7: Determination of nuclear STING interactome using mass spectrometry.
Fig. 8: Clinical relevance of STING in breast cancer.

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Acknowledgements

This study was funded by XenTech, annual funding from Inserm and the University Paris Descartes, and ECLER non-profit association. JG and LC were recipient of a CIFRE fellowship from the Association Nationale de la Recherche et de la Technologie (ANRT). MM is supported by the Ligue Nationale contre le Cancer. We are grateful to Patrice Codogno, Etienne Morel, Ganna Panasyuk, Thierry Dubois and Frédéric Rieux-Laucat for helpful discussions, to Dr Orgunc and Pr S. Fillatreau for providing biological materials, and to Katheryn Meek for critical reading of the manuscript.

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Conception and design: LC, JG, SC, VG. Development of methodology: LC, ICG, NG, AS, SC, VG. Acquisition of data: LC, ICG, AS, VJ, MP. Analysis and interpretation of data: LC, ICG, NG, AS, NR-R, MM, SC, VG. Writing, review, and/or revision of the manuscript: LC, ICG, AS, MM, J-GJ, SC, VG. Administrative, technical, or material support: LC, ICG, AS, VJ, NR-R, J-GJ, SC, VG. Study supervision: SC, VG.

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Correspondence to Vincent Goffin.

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Cheradame, L., Guerrera, I.C., Gaston, J. et al. STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway. Oncogene (2021). https://doi.org/10.1038/s41388-021-02037-4

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