Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 7, Pages 2447-2452Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1316848111
Keywords
mechanobiology; breast cancer; metastasis
Categories
Funding
- National Cancer Institute [R21CA140096, R33CA174550]
- Singapore-Massachusetts Institute of Technology Alliance for Research and Technology
- Department of Defense Breast Cancer Innovator Award [BC074986]
- National Science Foundation Graduate Research Fellowships
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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 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.
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