title: Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer.
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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Boire
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Valiente
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ekrem Emrah
authors.initials: EE
authors.lastname: Er
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lopez-Soto
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Leni
authors.initials: L
authors.lastname: Jacob
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ruzeen
authors.initials: R
authors.lastname: Patwa
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hardik
authors.initials: H
authors.lastname: Shah
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018031:Connexin 43 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology; D008469:Meclofenamic Acid / Q000494:pharmacology / Q000627:therapeutic use; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects; D000091363:Protocadherins; D050794:STAT1 Transcription Factor / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099197:STING Protein
chemical_list: D001549:Benzamides; D001578:Benzopyrans; D015820:Cadherins; D018031:Connexin 43; D016898:Interferon-alpha; D008469:Meclofenamic Acid; D008565:Membrane Proteins; D016328:NF-kappa B; D009712:Nucleotides, Cyclic; D000091363:Protocadherins; D050794:STAT1 Transcription Factor; D048069:Tumor Necrosis Factors; C113391:PCDH7 protein, human; C000608439:PCDH7 protein, mouse; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C118706:tonabersat