Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer

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 and Joan Massagué ()
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Qing Chen: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Adrienne Boire: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Xin Jin: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Manuel Valiente: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
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
Leni S. Jacob: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
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

Nature, 2016, vol. 533, issue 7604, 493-498

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature18268

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