Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer

被引：766

作者：

Chen, Qing ^{[1
,5
]}

Boire, Adrienne ^{[1
,2
]}

Jin, Xin ^{[1
,6
]}

Valiente, Manuel ^{[1
,7
]}

Er, Ekrem Emrah ^{[1
]}

Lopez-Soto, Alejandro ^{[1
,8
]}

Jacob, Leni S. ^{[1
,9
]}

Patwa, Ruzeen ^{[1
]}

Shah, Hardik ^{[3
]}

Xu, Ke ^{[4
]}

Cross, Justin R. ^{[3
]}

Massague, Joan ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Donald B & Catherine C Marron Canc Metab Ctr, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Mol Cytol Core Facil, New York, NY 10065 USA

[5] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA

[6] Eli & Edythe L Broad Inst, Canc Program, Cambridge, MA 02142 USA

[7] Spanish Natl Canc Res Ctr CNIO, Brain Metastasis Grp, E-28029 Madrid, Spain

[8] Univ Oviedo, Fac Med, Dept Funct Biol IUOPA, Oriedo 33006, Spain

[9] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Genet, 3 Blackfan Circle,CLS 417, Boston, MA 02115 USA

来源：

NATURE | 2016年 / 533卷 / 7604期

关键词：

BREAST-CANCER METASTASIS; CADHERIN SUPERFAMILY; EXPRESSION ANALYSIS; TUMOR-CELLS; GENES; CONNEXIN; CLASSIFICATION; RECOGNITION; SURVIVAL; PATHWAY;

D O I：

10.1038/nature18268

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-alpha (IFN alpha) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-kappa B 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.

引用

页码：493 / +

页数：19

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