Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer

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. A heterotypic cell interaction between astrocytes and tumour cells colonizing the brain is discovered; by establishing gap junctions, tumour cells trigger the activation of innate immune response signalling in astrocytes, which results in the secretion of factors that support growth and chemoresistance in brain metastatic cells. The development of novel therapeutic approaches to brain metastases has been hampered by a lack of mechanistic insights. These authors report that invasive breast and lung cancer cells engage the normally protective network of brain astrocytes to support metastases. By establishing gap junctions, tumour cells trigger the activation of innate immune response signalling in astrocytes, which then secrete factors that support metastatic growth and chemoresistance. The gap junction inhibitors meclofenamate and tonabersat interfere with this paracrine loop and impair the growth of experimental brain metastases, suggesting possible clinical relevance.