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Nature. 2016 May 26;533(7604):493-498. doi: 10.1038/nature18268. Epub 2016 May 18.

Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
#
Contributed equally

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.

PMID:
27225120
PMCID:
PMC5021195
DOI:
10.1038/nature18268
[Indexed for MEDLINE]
Free PMC Article

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