Fluid shear stress activates YAP1 to promote cancer cell motility

Nat Commun. 2017 Jan 18;8:14122. doi: 10.1038/ncomms14122.

Abstract

Mechanical stress is pervasive in egress routes of malignancy, yet the intrinsic effects of force on tumour cells remain poorly understood. Here, we demonstrate that frictional force characteristic of flow in the lymphatics stimulates YAP1 to drive cancer cell migration; whereas intensities of fluid wall shear stress (WSS) typical of venous or arterial flow inhibit taxis. YAP1, but not TAZ, is strictly required for WSS-enhanced cell movement, as blockade of YAP1, TEAD1-4 or the YAP1-TEAD interaction reduces cellular velocity to levels observed without flow. Silencing of TEAD phenocopies loss of YAP1, implicating transcriptional transactivation function in mediating force-enhanced cell migration. WSS dictates expression of a network of YAP1 effectors with executive roles in invasion, chemotaxis and adhesion downstream of the ROCK-LIMK-cofilin signalling axis. Altogether, these data implicate YAP1 as a fluid mechanosensor that functions to regulate genes that promote metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors / genetics
  • Actin Depolymerizing Factors / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Movement*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Extracellular Fluid / chemistry*
  • Extracellular Fluid / metabolism
  • Humans
  • Lim Kinases / genetics
  • Lim Kinases / metabolism
  • Lymphatic Vessels / chemistry
  • Lymphatic Vessels / metabolism
  • Male
  • Mechanotransduction, Cellular
  • Mice
  • Mice, Nude
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / physiopathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Signal Transduction
  • Stress, Mechanical*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Actin Depolymerizing Factors
  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • TEAD1 protein, human
  • TEAD2 protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • LIMK1 protein, human
  • Lim Kinases