title: 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.
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue New York, New York 10065, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Furlow
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue New York, New York 10065, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: T David
authors.initials: TD
authors.lastname: Soong
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue New York, New York 10065, USA.
authors.forename: Nils
authors.initials: N
authors.lastname: Halberg
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue New York, New York 10065, USA.
authors.forename: Hani
authors.initials: H
authors.lastname: Goodarzi
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue New York, New York 10065, USA.
authors.forename: Creed
authors.initials: C
authors.lastname: Mangrum
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue New York, New York 10065, USA.
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue New York, New York 10065, USA.
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D017630:Connexins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009154:Mutation; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D054852:Small Molecule Libraries / Q000494:pharmacology; D013314:Stress, Mechanical; D059467:Transcriptome; D014183:Transplantation, Heterologous
chemical_list: D017630:Connexins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate