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Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles |
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| Authors: | Maren Voglstaetter Andreas R Thomsen Jerome Nouvel Arend Koch Paul Jank Elena Grueso Navarro Tanja Gainey-Schleicher Richa Khanduri Andrea Groß Florian Rossner Carina Blaue Clemens M Franz Marina Veil Gerhard Puetz Andreas Hippe Jochen Dindorf Jubin Kashef Wilko Thiele Bernhard Homey Celine Greco Claude Boucheix Andreas Baur Thalia Erbes Cornelius F Waller Marie Follo Ghamartaj Hossein Christine Sers Jonathan Sleeman Irina Nazarenko |
| Affiliation: | 1. Institute for Infection Prevention and Hospital Epidemiology;2. Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany;3. Institute of Neuropathology, Charité Universitätsmedizin Berlin, Berlin, Germany;4. Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany;5. Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany;6. DFG-Center for Functional Nanostructures, Karlsruhe Institute of Technology, Karlsruhe, Germany;7. Institute of Clinical Chemistry and Laboratory Medicine, University of Freiburg, Freiburg im Breisgau, Germany;8. Department of Dermatology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany;9. Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany Department of Dermatology, University Hospital Erlangen, Erlangen, Germany Translational Research Center, Friedrich-Alexander-University of Erlangen-Nuernberg, Erlangen, Germany;10. Institute for Photon Science and Synchrotron Radiation, Karlsruhe Institute of Technology (KIT), Eggenstein-Leopoldshafen, Germany;11. Medical Faculty, University of Heidelberg, Mannheim, Germany;12. UMR-S935, Inserm, Université Paris Sud, Université Paris Saclay, Villejuif, France Department of Pain Management and Palliative Care, Necker Hospital, Paris, France;13. Department of Dermatology, University Hospital Erlangen, Erlangen, Germany Translational Research Center, Friedrich-Alexander-University of Erlangen-Nuernberg, Erlangen, Germany;14. Department of Gynecology and Obstetrics, Faculty of Medicine, University of Freiburg, Freiburg, Germany;15. Department of Medicine I, Medical Center, University of Freiburg, Freiburg, Germany Faculty of Medicine, University of Freiburg, Freiburg, Germany;16. Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Department of Animal Physiology, Laboratory of Developmental Biology, University of Tehran, Tehran, Iran;17. Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany Medical Faculty, University of Heidelberg, Mannheim, Germany |
| Abstract: | Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8+ tumours formed multiple liver and spleen metastases, while Tspan8− tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up-regulation of E-cadherin and down-regulation of Twist, p120-catenin, and β-catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal–epithelial transition. Furthermore, Tspan8+ cells exhibited enhanced cell–cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several-fold increase in EV number in cell culture and the circulation of tumour-bearing animals. We observed increased protein levels of E-cadherin and p120-catenin in these EVs; furthermore, Tspan8 and p120-catenin were co-immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
| Keywords: | breast cancer Tspan8 mesenchymal–epithelial transition beta-catenin signalling pathway tetraspanins extracellular vesicles metastases three-dimensional cell culture |