IQGAP1 and NWASP promote human cancer cell dissemination and metastasis by regulating β1-integrin via FAK and MRTF/SRF
Camilla Cerutti,
Serena Lucotti,
Sofia T. Menendez,
Nicolas Reymond,
Ritu Garg,
Ignacio A. Romero,
Ruth Muschel,
Anne J. Ridley
Affiliations
Camilla Cerutti
School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK; Randall Centre for Cell and Molecular Biophysics, King’s College London, London SE1 U1L, UK; Department of Life Sciences, Centre for Inflammation Research and Translational Medicine (CIRTM), Brunel University London, Uxbridge UB8 3PH, UK; Corresponding author
Serena Lucotti
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK
Sofia T. Menendez
Randall Centre for Cell and Molecular Biophysics, King’s College London, London SE1 U1L, UK
Nicolas Reymond
Randall Centre for Cell and Molecular Biophysics, King’s College London, London SE1 U1L, UK
Ritu Garg
Randall Centre for Cell and Molecular Biophysics, King’s College London, London SE1 U1L, UK
Ignacio A. Romero
School of Life, Health and Chemical Sciences, The Open University, Milton Keynes MK7 6AA, UK
Ruth Muschel
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK
Anne J. Ridley
School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK; Randall Centre for Cell and Molecular Biophysics, King’s College London, London SE1 U1L, UK; Corresponding author
Summary: Attachment of circulating tumor cells to the endothelial cells (ECs) lining blood vessels is a critical step in cancer metastatic colonization, which leads to metastatic outgrowth. Breast and prostate cancers are common malignancies in women and men, respectively. Here, we observe that β1-integrin is required for human prostate and breast cancer cell adhesion to ECs under shear-stress conditions in vitro and to lung blood vessel ECs in vivo. We identify IQGAP1 and neural Wiskott-Aldrich syndrome protein (NWASP) as regulators of β1-integrin transcription and protein expression in prostate and breast cancer cells. IQGAP1 and NWASP depletion in cancer cells decreases adhesion to ECs in vitro and retention in the lung vasculature and metastatic lung nodule formation in vivo. Mechanistically, NWASP and IQGAP1 act downstream of Cdc42 to increase β1-integrin expression both via extracellular signal-regulated kinase (ERK)/focal adhesion kinase signaling at the protein level and by myocardin-related transcription factor/serum response factor (SRF) transcriptionally. Our results identify IQGAP1 and NWASP as potential therapeutic targets to reduce early metastatic dissemination.
