Podoplanin drives dedifferentiation and amoeboid invasion of melanoma
Charlotte M. de Winde,
Samantha L. George,
Eva Crosas-Molist,
Yukti Hari-Gupta,
Abbey B. Arp,
Agnesska C. Benjamin,
Lindsey J. Millward,
Spyridon Makris,
Alexander Carver,
Valerio Imperatore,
Víctor G. Martínez,
Victoria Sanz-Moreno,
Sophie E. Acton
Affiliations
Charlotte M. de Winde
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Samantha L. George
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Barts Cancer Institute, John Vane Science Building, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UK
Eva Crosas-Molist
Barts Cancer Institute, John Vane Science Building, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UK
Yukti Hari-Gupta
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Abbey B. Arp
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Agnesska C. Benjamin
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Lindsey J. Millward
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Spyridon Makris
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Alexander Carver
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Valerio Imperatore
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Cell Biogenesis and Tissue Regeneration Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Víctor G. Martínez
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Victoria Sanz-Moreno
Barts Cancer Institute, John Vane Science Building, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UK
Sophie E. Acton
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Corresponding author
Summary: Melanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease. Melanoma cells utilize amoeboid migration as mode of local invasion. Amoeboid invasion is characterized by rounded cell morphology and high actomyosin contractility driven by Rho GTPase signalling. Migrastatic drugs targeting actin polymerization and contractility are therefore a promising treatment option for metastatic melanoma. To predict amoeboid invasion and metastatic potential, biomarkers functionally linked to contractility pathways are needed. The glycoprotein podoplanin drives actomyosin contractility in lymphoid fibroblasts and is overexpressed in many cancers. We show that podoplanin enhances amoeboid invasion in melanoma. Podoplanin expression in murine melanoma drives rounded cell morphology, increasing motility, and invasion in vivo. Podoplanin expression is increased in a subset of dedifferentiated human melanoma, and in vitro is sufficient to upregulate melanoma-associated marker Pou3f2/Brn2. Together, our data define podoplanin as a functional biomarker for dedifferentiated invasive melanoma and a promising migrastatic therapeutic target.
