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Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and experimental metastasis

Souhila Medjkane1, Cristina Perez-Sanchez, Cedric Gaggioli

  • 1Transcription Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.

Nature Cell Biology
|February 10, 2009
PubMed

Insights

The MRTF-SRF pathway, regulated by Rho GTPases, is crucial for cancer cell invasion and metastasis. This pathway controls cytoskeletal dynamics, impacting cell adhesion, motility, and lung colonization.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Rho GTPases regulate cytoskeletal dynamics and transcriptional activation via MRTF-SRF.
  • The MRTF-SRF pathway is a key mediator of Rho GTPase signaling.
  • Basal MRTF-SRF activity is Rho-dependent in breast carcinoma and melanoma cells.

Purpose of the Study:

  • To investigate the role of the MRTF-SRF pathway in cytoskeletal dynamics and cancer cell metastasis.
  • To determine the impact of MRTF-SRF pathway disruption on cell adhesion, invasion, and colonization.

Main Methods:

  • RNA interference (RNAi) was used to deplete MRTFs or SRF in MDA-MB-231 breast carcinoma and B16F2 melanoma cells.
  • Cellular behaviors such as adhesion, spreading, invasion, motility, proliferation, and apoptosis were assessed.
  • Tumor cell xenografts were used to evaluate the effect of MRTF/SRF depletion on tumor cell motility and lung colonization in vivo.

Main Results:

  • Depletion of MRTFs or SRF reduced cell adhesion, spreading, invasion, and motility in vitro.
  • MRTF/SRF-depleted tumor xenografts exhibited reduced cell motility but normal proliferation.
  • Tumor cells lacking MRTF or SRF failed to colonize the lung, indicating impaired metastatic potential.
  • MYH9 and MYL9 were identified as MRTF-dependent genes essential for invasion and lung colonization.
  • Overexpression of activated MAL/MRTF-A enhanced lung colonization in poorly metastatic cells.

Conclusions:

  • The Rho-dependent MRTF-SRF pathway is essential for actin-based cell behaviors critical for experimental metastasis.
  • Disruption of the MRTF-SRF network impairs cancer cell invasion and the ability to colonize distant organs, specifically the lungs.
  • The pathway's components, including MYH9 and MYL9, are vital for cancer cell metastatic dissemination.

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