TRPM7 controls mesenchymal features of breast cancer cells by tensional regulation of SOX4

Arthur J Kuipers, Jeroen Middelbeek, Kirsten Vrenken, Carlos Pérez-González, Geert Poelmans, Jeffrey Klarenbeek, Kees Jalink, Xavier Trepat, Frank N van Leeuwen

Research output: Contribution to journalArticlepeer-review

Abstract

Mechanically induced signaling pathways are important drivers of tumor progression. However, if and how mechanical signals affect metastasis or therapy response remains poorly understood. We previously found that the channel-kinase TRPM7, a regulator of cellular tension implicated in mechano-sensory processes, is required for breast cancer metastasis in vitro and in vivo. Here, we show that TRPM7 contributes to maintaining a mesenchymal phenotype in breast cancer cells by tensional regulation of the EMT transcription factor SOX4. The functional consequences of SOX4 knockdown closely mirror those produced by TRPM7 knockdown. By traction force measurements, we demonstrate that TRPM7 reduces cytoskeletal tension through inhibition of myosin II activity. Moreover, we show that SOX4 expression and downstream mesenchymal markers are inversely regulated by cytoskeletal tension and matrix rigidity. Overall, our results identify SOX4 as a transcription factor that is uniquely sensitive to cellular tension and indicate that TRPM7 may contribute to breast cancer progression by tensional regulation of SOX4.

Original languageEnglish
Pages (from-to)2409-2419
Number of pages11
JournalBiochimica et biophysica acta. Molecular basis of disease
Volume1864
Issue number7
DOIs
Publication statusPublished - Jul 2018

Keywords

  • Breast Neoplasms/genetics
  • Cell Line, Tumor
  • Cytoskeleton/genetics
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Myosin Type II/genetics
  • Neoplasm Proteins/genetics
  • Protein Serine-Threonine Kinases/genetics
  • SOXC Transcription Factors/genetics
  • TRPM Cation Channels/genetics
  • Tensile Strength

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