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Vol. 19, Issue 5, 2003-2013, May 2008

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Stathmin Activity Influences Sarcoma Cell Shape, Motility, and Metastatic Potential

Barbara Belletti^*,, Milena S. Nicoloso^*,,, Monica Schiappacassi^*, Stefania Berton^*, Francesca Lovat^*, Katarina Wolf^,||, Vincenzo Canzonieri^¶, Sara D'Andrea^*, Antonella Zucchetto^#, Peter Friedl^,||, Alfonso Colombatti^*,@,, and Gustavo Baldassarre^*

*Division of Experimental Oncology 2, ^¶Division of Pathology, and ^#Clinical and Experimental Hematology Research Unit, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS Aviano 33081, Italy; Rudolf-Virchow Center, Deutsche Forschungsgemeinschaft Center for Experimental Biomedicine and Department of Dermatology, University of Wuerzburg, 97080 Wuerzburg, Germany; and ^@Dipartimento di Scienze e Tecnologie Biomediche and MATI Center of Excellence, University of Udine, 33100 Udine, Italy

Submitted September 12, 2007; Revised February 13, 2008; Accepted February 15, 2008
Monitoring Editor: Josephine Adams

The balanced activity of microtubule-stabilizing and -destabilizing proteins determines the extent of microtubule dynamics, which is implicated in many cellular processes, including adhesion, migration, and morphology. Among the destabilizing proteins, stathmin is overexpressed in different human malignancies and has been recently linked to the regulation of cell motility. The observation that stathmin was overexpressed in human recurrent and metastatic sarcomas prompted us to investigate stathmin contribution to tumor local invasiveness and distant dissemination. We found that stathmin stimulated cell motility in and through the extracellular matrix (ECM) in vitro and increased the metastatic potential of sarcoma cells in vivo. On contact with the ECM, stathmin was negatively regulated by phosphorylation. Accordingly, a less phosphorylable stathmin point mutant impaired ECM-induced microtubule stabilization and conferred a higher invasive potential, inducing a rounded cell shape coupled with amoeboid-like motility in three-dimensional matrices. Our results indicate that stathmin plays a significant role in tumor metastasis formation, a finding that could lead to exploitation of stathmin as a target of new antimetastatic drugs.

These authors contributed equally to this work.

Present addresses: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX;

^|| Department of Cell Biology, NCMLS Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Address correspondence to: Gustavo Baldassarre (gbaldassarre{at}cro.it)