Polacheck, William J.German, Alexandra E.Mammoto, AkikoIngber, Donald E.Kamm, Roger D.2019-10-032014Polacheck, W. J., A. E. German, A. Mammoto, D. E. Ingber, and R. D. Kamm. 2014. “Mechanotransduction of Fluid Stresses Governs 3D Cell Migration.” Proceedings of the National Academy of Sciences 111 (7): 2447–52. https://doi.org/10.1073/pnas.1316848111.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41461199Solid 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 similar to 3 mu m/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 beta 1-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.en-USJournal Article2019-10-0310.1073/pnas.1316848111