title: Activating the nuclear piston mechanism of 3D migration in tumor cells.
abstract: Primary human fibroblasts have the remarkable ability to use their nucleus like a piston, switching from low- to high-pressure protrusions in response to the surrounding three-dimensional (3D) matrix. Although migrating tumor cells can also change how they migrate in response to the 3D matrix, it is not clear if they can switch between high- and low-pressure protrusions like primary fibroblasts. We report that unlike primary fibroblasts, the nuclear piston is not active in fibrosarcoma cells. Protease inhibition rescued the nuclear piston mechanism in polarized HT1080 and SW684 cells and generated compartmentalized pressure. Achieving compartmentalized pressure required the nucleoskeleton-cytoskeleton linker protein nesprin 3, actomyosin contractility, and integrin-mediated adhesion, consistent with lobopodia-based fibroblast migration. In addition, this activation of the nuclear piston mechanism slowed the 3D movement of HT1080 cells. Together, these data indicate that inhibiting protease activity during polarized tumor cell 3D migration is sufficient to restore the nuclear piston migration mechanism with compartmentalized pressure characteristic of nonmalignant cells.
authors.affiliation: Department of Biology, Drexel University, Philadelphia, PA 19104 rjp336@drexel.edu.
authors.forename: Ryan J
authors.identifier: http://orcid.org/0000-0001-9780-4969
authors.initials: RJ
authors.lastname: Petrie
authors.affiliation: Department of Biology, Drexel University, Philadelphia, PA 19104.
authors.forename: Heather M
authors.identifier: http://orcid.org/0000-0003-1361-2789
authors.initials: HM
authors.lastname: Harlin
authors.affiliation: Department of Biology, Drexel University, Philadelphia, PA 19104.
authors.forename: Lulu I T
authors.identifier: http://orcid.org/0000-0001-7662-3448
authors.initials: LI
authors.lastname: Korsak
authors.affiliation: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Kenneth M
authors.identifier: http://orcid.org/0000-0003-1512-6805
authors.initials: KM
authors.lastname: Yamada
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016764:Cell Polarity; D048430:Cell Shape; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D011312:Pressure; D061251:Primary Cell Culture; D011480:Protease Inhibitors / Q000494:pharmacology; D011554:Pseudopodia / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D014162:Transfection
chemical_list: D016023:Integrins; D061965:Matrix Metalloproteinase Inhibitors; D008840:Microfilament Proteins; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; C529565:SYNE3 protein, human; D000205:Actomyosin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14