Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival.
Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival.
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DOI：
10.1038/ncb3194
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发表时间：
2015-07
影响因子：
21.3
通讯作者：
Tavazoie SF
中科院分区：
文献类型：
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作者：
Furlow PW;Zhang S;Soong TD;Halberg N;Goodarzi H;Mangrum C;Wu YG;Elemento O;Tavazoie SF
在转移进展过程中，循环癌细胞滞留在终末器官的微血管系统内，其中大多数死于机械变形。虽然这种现象在半个多世纪前就被首次描述，但使某些细胞能够在这种转移抑制屏障中存活的机制仍然未知。通过将全转录组RNA测序（RNA-seq）技术应用于具有不同转移能力的同基因癌细胞，我们鉴定了编码截短形式的泛连接蛋白-1（PANX 1）通道PANX 11 -89的突变，其在高转移性乳腺癌细胞中反复富集。PANX 11 -89通过增加由膜拉伸激活的机械敏感性PANX 1通道的ATP释放，发挥允许转移性细胞在微脉管系统中的创伤性变形期间存活的功能。PANX 1介导的ATP释放通过P2 γ-嘌呤能受体作为变形诱导的细胞凋亡的自分泌抑制剂。最后，发现PANX 1通道的小分子治疗性抑制降低了乳腺癌转移的效率。这些数据表明微血管诱导的生物力学创伤后转移细胞存活的分子基础。
During metastatic progression, circulating cancer cells become lodged within the microvasculature of end-organs, where a majority die from mechanical deformation. Though this phenomenon was first described over a half-century ago, the mechanisms enabling certain cells to survive this metastasis-suppressive barrier remain unknown. By applying whole-transcriptome RNA-sequencing (RNA-seq) technology to isogenic cancer cells of differing metastatic capacity, we identified a mutation encoding a truncated form of the pannexin-1 (PANX1) channel, PANX1 1–89, as recurrently enriched in highly metastatic breast cancer cells. PANX1 1–89 functions to permit metastatic cell survival during traumatic deformation in the microvasculature by augmenting ATP release from mechanosensitive PANX1 channels activated by membrane stretch. PANX1-mediated ATP release acts as an autocrine suppressor of deformation-induced apoptosis via P2y-purinergic receptors. Finally, small-molecule therapeutic inhibition of PANX1 channels is found to reduce the efficiency of breast cancer metastasis. These data suggest a molecular basis for metastatic cell survival upon microvasculature-induced biomechanical trauma.