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Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival.


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.

SUBMITTER: Furlow PW 

PROVIDER: S-EPMC5310712 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival.

Furlow Paul W PW   Zhang Steven S   Soong T David TD   Halberg Nils N   Goodarzi Hani H   Mangrum Creed C   Wu Y Gloria YG   Elemento Olivier O   Tavazoie Sohail F SF  

Nature cell biology 20150622 7


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  ...[more]

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