Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts

Nat Cell Biol. 2013 Jun;15(6):637-46. doi: 10.1038/ncb2756. Epub 2013 May 26.

Abstract

To learn more about cancer-associated fibroblasts (CAFs), we have isolated fibroblasts from different stages of breast cancer progression and analysed their function and gene expression. These analyses reveal that activation of the YAP transcription factor is a signature feature of CAFs. YAP function is required for CAFs to promote matrix stiffening, cancer cell invasion and angiogenesis. Remodelling of the ECM and promotion of cancer cell invasion requires the actomyosin cytoskeleton. YAP regulates the expression of several cytoskeletal regulators, including ANLN and DIAPH3, and controls the protein levels of MYL9 (also known as MLC2). Matrix stiffening further enhances YAP activation, thus establishing a feed-forward self-reinforcing loop that helps to maintain the CAF phenotype. Actomyosin contractility and Src function are required for YAP activation by stiff matrices. Further, transient ROCK inhibition is able to disrupt the feed-forward loop, leading to a long-lasting reversion of the CAF phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton
  • Actomyosin / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Breast Neoplasms / metabolism*
  • Cell Cycle Proteins
  • Cells, Cultured
  • Disease Progression
  • Enzyme Activation
  • Extracellular Matrix / metabolism
  • Female
  • Fibroblasts / physiology*
  • Focal Adhesions
  • Humans
  • Mechanotransduction, Cellular*
  • Mice
  • Microscopy, Atomic Force
  • Microtubule-Associated Proteins / metabolism
  • Myosin Light Chains
  • NADPH Dehydrogenase / metabolism
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering
  • rho-Associated Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Microtubule-Associated Proteins
  • Mylpf protein, mouse
  • Myosin Light Chains
  • Phosphoproteins
  • RNA, Small Interfering
  • Yap protein, mouse
  • Actomyosin
  • Dia2 protein, mouse
  • NADPH Dehydrogenase
  • src-Family Kinases
  • rho-Associated Kinases