Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival.

TitleMechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival.
Publication TypeJournal Article
Year of Publication2015
AuthorsFurlow PW, Zhang S, T Soong D, Halberg N, Goodarzi H, Mangrum C, Y Wu G, Elemento O, Tavazoie SF
JournalNat Cell Biol
Date Published2015 Jul
KeywordsAdenosine Triphosphate, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Cells, Cultured, Connexins, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Immunoblotting, Interleukin Receptor Common gamma Subunit, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Microscopy, Confocal, Mutation, Neoplasm Metastasis, Neovascularization, Pathologic, Nerve Tissue Proteins, Oligonucleotide Array Sequence Analysis, RNA Interference, Small Molecule Libraries, Stress, Mechanical, Transcriptome, Transplantation, Heterologous

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.

Alternate JournalNat. Cell Biol.
PubMed ID26098574
PubMed Central IDPMC5310712
Grant ListT32 GM007739 / GM / NIGMS NIH HHS / United States
GM07739 / GM / NIGMS NIH HHS / United States