Article | Published:

Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer

Nature volume 533, pages 493498 (26 May 2016) | Download Citation

  • A Corrigendum to this article was published on 29 March 2017

Abstract

Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma–astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.

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Gene Expression Omnibus

Data deposits

RNA-seq data have been deposited in NCBI Gene Expression Omnibus (GEO) under accession number GSE79256.

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Acknowledgements

We thank D. Macalinao and other members of the Massagué laboratory for discussions. This work was supported by NIH grants P01-CA129243, U54-163167 and P30 CA008748, DOD Innovator award W81XWH-12-0074, the Alan and Sandra Gerry Metastasis Research Initiative (J.M.), the MSKCC Clinical Scholars Training Program (A.B.), the Solomon R. and Rebecca D. Baker Foundation (A.B), and by the Susan G. Komen Organization (X.J.).

Author information

Author notes

    • Qing Chen
    • , Xin Jin
    • , Manuel Valiente
    • , Alejandro Lopez-Soto
    •  & Leni S. Jacob

    Present addresses: The Wistar Institute 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA (Q.C.); Cancer Program, The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts 02142, USA (X.J.); Brain Metastasis Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain (M.V.); Department of Functional Biology IUOPA, University of Oviedo, Facultad de Medicina, 33006 Oriedo, Spain (A.L.-S.); Department of Genetics, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS 417, Boston, Massachusetts 02115, USA (L.J.).

    • Qing Chen
    •  & Adrienne Boire

    These authors contributed equally to this work.

Affiliations

  1. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Qing Chen
    • , Adrienne Boire
    • , Xin Jin
    • , Manuel Valiente
    • , Ekrem Emrah Er
    • , Alejandro Lopez-Soto
    • , Leni S. Jacob
    • , Ruzeen Patwa
    •  & Joan Massagué
  2. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Adrienne Boire
  3. Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Hardik Shah
    •  & Justin R. Cross
  4. Molecular Cytology Core Facility Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Ke Xu

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Contributions

Q.C., A.B. and J.M. conceptualized the project and designed the experiments. Q.C. and A.B. performed the experiments. X.J., M.V., E.E.E., A.L.-S., L.J. and R.P. assisted with the experiments and bioinformatics analysis. H.S. and J.R.C. performed the LC–MS/MS analysis, and K.X. the time-lapse confocal imaging. A.B., Q.C. and J.M. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joan Massagué.

Reviewer Information Nature thanks R. Hynes and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Table 1

    The file shows the target sequences of shRNAs.

Videos

  1. 1.

    Dye transfer from MDA231-BrM2 cells and astrocytes

    MDA231-BrM2 cells with Calcein Red-Orange dye. A single-cell suspension of labeled cancer cells was added to the monolayer cultured astrocytes. Bright field and red fluorescent images in the same region were captured every 20 minutes.

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DOI

https://doi.org/10.1038/nature18268

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