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Nat Cell Biol. 2015 Jul;17(7):943-52. doi: 10.1038/ncb3194. Epub 2015 Jun 22.

Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival.

Author information

1
Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue New York, New York 10065, USA.
2
HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA.

Abstract

During metastatic progression, circulating cancer cells become lodged within the microvasculature of end organs, where most die from mechanical deformation. Although 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 technology to isogenic cancer cells of differing metastatic capacities, 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 through 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 on microvasculature-induced biomechanical trauma.

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PMID:
26098574
PMCID:
PMC5310712
DOI:
10.1038/ncb3194
[Indexed for MEDLINE]
Free PMC Article

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