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Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer

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  • Qing Chen

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
    † 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.).)

  • Adrienne Boire

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Xin Jin

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
    † 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.).)

  • Manuel Valiente

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
    † 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.).)

  • Ekrem Emrah Er

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center)

  • Alejandro Lopez-Soto

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
    † 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.).)

  • Leni S. Jacob

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
    † 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.).)

  • Ruzeen Patwa

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center)

  • Hardik Shah

    (Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center)

  • Ke Xu

    (Molecular Cytology Core Facility Memorial Sloan Kettering Cancer Center)

  • Justin R. Cross

    (Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center)

  • Joan Massagué

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center)

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.

Suggested Citation

  • Qing Chen & Adrienne Boire & Xin Jin & Manuel Valiente & Ekrem Emrah Er & Alejandro Lopez-Soto & Leni S. Jacob & Ruzeen Patwa & Hardik Shah & Ke Xu & Justin R. Cross & Joan Massagué, 2016. "Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer," Nature, Nature, vol. 533(7604), pages 493-498, May.
    • Handle: RePEc:nat:nature:v:533:y:2016:i:7604:d:10.1038_nature18268
    DOI: 10.1038/nature18268
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    Cited by:

    1. Yu-Hsuan Chen & Han-Hsiun Chen & Won-Jing Wang & Hsin-Yi Chen & Wei-Syun Huang & Chien-Han Kao & Sin-Rong Lee & Nai Yang Yeat & Ruei-Liang Yan & Shu-Jou Chan & Kuen-Phon Wu & Ruey-Hwa Chen, 2023. "TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Chen Ni & Xiaohan Lou & Xiaohan Yao & Linlin Wang & Jiajia Wan & Xixi Duan & Jialu Liang & Kaili Zhang & Yuanyuan Yang & Li Zhang & Chanjun Sun & Zhenzhen Li & Ming Wang & Linyu Zhu & Dekang Lv & Zhih, 2022. "ZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Weili Ma & Maria Cecília Oliveira-Nunes & Ke Xu & Andrew Kossenkov & Benjamin C. Reiner & Richard C. Crist & James Hayden & Qing Chen, 2023. "Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Zikun Ma & Zhiyong Li & Yize Mao & Jingwei Ye & Zefu Liu & Yuzhao Wang & Chen Wei & Jun Cui & Zhuowei Liu & Xiaoyu Liang, 2023. "AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Bo Jiang & Xiaozhi Zhao & Wei Chen & Wenli Diao & Meng Ding & Haixiang Qin & Binghua Li & Wenmin Cao & Wei Chen & Yao Fu & Kuiqiang He & Jie Gao & Mengxia Chen & Tingsheng Lin & Yongming Deng & Chao Y, 2022. "Lysosomal protein transmembrane 5 promotes lung-specific metastasis by regulating BMPR1A lysosomal degradation," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Xianhui Ruan & Wei Yan & Minghui Cao & Ray Anthony M. Daza & Miranda Y. Fong & Kaifu Yang & Jun Wu & Xuxiang Liu & Melanie Palomares & Xiwei Wu & Arthur Li & Yuan Chen & Rahul Jandial & Nicholas C. Sp, 2024. "Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    8. Hongwei Lv & Qianni Zong & Cian Chen & Guishuai Lv & Wei Xiang & Fuxue Xing & Guoqing Jiang & Bing Yan & Xiaoyan Sun & Yue Ma & Liang Wang & Zixin Wu & Xiuliang Cui & Hongyang Wang & Wen Yang, 2024. "TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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