title: Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines.
abstract: Cancer cells are defined by their ability to invade through the basement membrane, a critical step during metastasis. While increased secretion of proteases, which facilitates degradation of the basement membrane, and alterations in the cytoskeletal architecture of cancer cells have been previously studied, the contribution of the mechanical properties of cells in invasion is unclear. Here, we applied a magnetic tweezer system to establish that stiffness of patient tumor cells and cancer cell lines inversely correlates with migration and invasion through three-dimensional basement membranes, a correlation known as a power law. We found that cancer cells with the highest migratory and invasive potential are five times less stiff than cells with the lowest migration and invasion potential. Moreover, decreasing cell stiffness by pharmacologic inhibition of myosin II increases invasiveness, whereas increasing cell stiffness by restoring expression of the metastasis suppressor TβRIII/betaglycan decreases invasiveness. These findings are the first demonstration of the power-law relation between the stiffness and the invasiveness of cancer cells and show that mechanical phenotypes can be used to grade the metastatic potential of cell populations with the potential for single cell grading. The measurement of a mechanical phenotype, taking minutes rather than hours needed for invasion assays, is promising as a quantitative diagnostic method and as a discovery tool for therapeutics. By showing that altering stiffness predictably alters invasiveness, our results indicate that pathways regulating these mechanical phenotypes are novel targets for molecular therapy of cancer.
authors.affiliation: Department of Physics and Astronomy, UNC-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Vinay
authors.initials: V
authors.lastname: Swaminathan
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Mythreye
authors.forename: E Tim
authors.initials: ET
authors.lastname: O'Brien
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
authors.forename: Richard
authors.initials: R
authors.lastname: Superfine
mesh_terms: D000205:Actomyosin / Q000502:physiology; D001201:Ascites / Q000473:pathology; D045744:Cell Line, Tumor / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology; D003094:Collagen; D003187:Compliance; D004338:Drug Combinations; D015195:Drug Design; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D007797:Laminin; D008280:Magnetics / Q000295:instrumentation; D008846:Micromanipulation / Q000295:instrumentation; D018625:Microscopy, Atomic Force; D008863:Microspheres; D058990:Molecular Targeted Therapy; D024462:Myosin Type II / Q000037:antagonists & inhibitors / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology; D011509:Proteoglycans / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology
chemical_list: D004338:Drug Combinations; D006576:Heterocyclic Compounds, 4 or More Rings; D007797:Laminin; D009363:Neoplasm Proteins; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C059485:matrigel; C071736:betaglycan; C472645:blebbistatin; D003094:Collagen; D000205:Actomyosin; D024462:Myosin Type II