Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer Journal Article
| Authors: | Chen, Q.; Boire, A.; Jin, X.; Valiente, M.; Er, E. E.; Lopez-Soto, A.; Jacob, L. S.; Patwa, R.; Shah, H.; Xu, K.; Cross, J. R.; Massague, J. |
| Article 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. © 2016 Macmillan Publishers Limited. |
| Keywords: | alpha interferon; brain neoplasms; mouse; animal; cytology; metabolism; animals; mice; stat1 protein; lung neoplasms; astrocyte; membrane proteins; immunoglobulin enhancer binding protein; drug resistance; drug screening; pathology; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; breast neoplasms; lung tumor; breast tumor; nf-kappa b; membrane protein; tumor cell line; paracrine signaling; innate immunity; immunity, innate; cadherin; cadherins; interferon-alpha; tumor necrosis factor; astrocytes; coculture; coculture techniques; benzamide derivative; benzamides; paracrine communication; secondary; connexin 43; gap junction; gap junctions; tumor necrosis factors; stat1 transcription factor; drug effects; benzopyran derivative; meclofenamic acid; nucleotides, cyclic; humans; human; female; secretion (process); cyclic guanosine monophosphate-adenosine monophosphate; cyclic nucleotide; mpys protein, human; mpys protein, mouse; pcdh7 protein, human; pcdh7 protein, mouse; tonabersat; benzopyrans |
| Journal Title: | Nature |
| Volume: | 533 |
| Issue: | 7604 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2016-05-26 |
| Start Page: | 493 |
| End Page: | 498 |
| Language: | English |
| DOI: | 10.1038/nature18268 |
| PUBMED: | 27225120 |
| PROVIDER: | scopus |
| PMCID: | PMC5021195 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2016 -- Source: Scopus |
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