Strong fascin expression promotes metastasis independent of its F-actin bundling activity
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Lisa S. Heinz1,*, Stefanie Muhs1,*, Johanna Schiewek1, Saskia Grüb1, Marcus Nalaskowski1, Yuan-Na Lin1,6, Harriet Wikman2, Leticia Oliveira-Ferrer3, Tobias Lange4, Jasmin Wellbrock5, Anja Konietzny7, Marina Mikhaylova7 and Sabine Windhorst1
1Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
4Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
6Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
7DFG Emmy Noether Group ‘Neuronal Protein Transport’, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
*These authors have contributed equally to this work
Sabine Windhorst, email: firstname.lastname@example.org
Keywords: fascin; metastasis; actin; microtubule; cytoskeletal dynamics
Received: April 21, 2017 Accepted: September 27, 2017 Published: November 01, 2017
High expression of the actin bundling protein Fascin increases the malignancy of tumor cells. Here we show that fascin expression is up-regulated in more malignant sub-cell lines of MDA-MB-231 cells as compared to parental cells. Since also parental MDA-MB-231 cells exhibit high fascin levels, increased fascin expression was termed as “hyperexpression”. To examine the effect of fascin hyperexpression, fascin was hyperexpressed in parental MDA-MB-231 cells and metastasis was analyzed in NOD scid gamma (NSG) mice. In addition, the effect of fascin mutants with inactive or constitutively active actin bundling activity was examined. Unexpectedly, we found that hyperexpression of both, wildtype (wt) and mutant fascin strongly increased metastasis in vivo, showing that the effect of fascin hyperexpression did not depend on its actin bundling activity. Cellular assays revealed that hyperexpression of wt and mutant fascin increased adhesion of MDA-MB-231 cells while transmigration and proliferation were not affected. Since it has been shown that fascin controls adhesion by directly interacting with microtubules (MTs), we analyzed if fascin hyperexpression affects MT dynamics. We found that at high concentrations fascin significantly increased MT dynamics in cells and in cell-free approaches. In summary our data show that strong expression of fascin in breast cancer cells increases metastasis independent of its actin bundling activity. Thus, it seems that the mechanism of fascin-stimulated metastasis depends on its concentration.
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