title: Mechanotransduction of fluid stresses governs 3D cell migration.
abstract: Solid tumors are characterized by high interstitial fluid pressure, which drives fluid efflux from the tumor core. Tumor-associated interstitial flow (IF) at a rate of ∼3 µm/s has been shown to induce cell migration in the upstream direction (rheotaxis). However, the molecular biophysical mechanism that underlies upstream cell polarization and rheotaxis remains unclear. We developed a microfluidic platform to investigate the effects of IF fluid stresses imparted on cells embedded within a collagen type I hydrogel, and we demonstrate that IF stresses result in a transcellular gradient in β1-integrin activation with vinculin, focal adhesion kinase (FAK), FAK(PY397), F actin, and paxillin-dependent protrusion formation localizing to the upstream side of the cell, where matrix adhesions are under maximum tension. This previously unknown mechanism is the result of a force balance between fluid drag on the cell and matrix adhesion tension and is therefore a fundamental, but previously unknown, stimulus for directing cell movement within porous extracellular matrix.
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: William J
authors.initials: WJ
authors.lastname: Polacheck
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: German
authors.forename: Akiko
authors.initials: A
authors.lastname: Mammoto
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kamm
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D045604:Extracellular Fluid / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D022001:Focal Adhesions / Q000502:physiology; D049452:Green Fluorescent Proteins; D006801:Humans; D057446:Hydrodynamics; D019012:Integrin beta1 / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D016596:Vinculin
chemical_list: D019012:Integrin beta1; D034741:RNA, Small Interfering; D016596:Vinculin; D049452:Green Fluorescent Proteins
keywords: breast cancer; mechanobiology; metastasis