Universität zu Köln

Steinestel, Konrad, Trautmann, Marcel ORCID: 0000-0002-5842-1196, Jansen, Esther-Pia, Dirksen, Uta, Rehkaemper, Jan, Mikesch, Jan-Henrik, Gerke, Julia S., Orth, Martin F., Sannino, Giuseppina, Arteaga, Maria-Francisca, Rossig, Claudia, Wardelmann, Eva, Gruenewald, Thomas G. P. and Hartmann, Wolfgang (2020). Focal adhesion kinase confers pro-migratory and antiapoptotic properties and is a potential therapeutic target in Ewing sarcoma. Mol. Oncol., 14 (2). S. 248 - 261. HOBOKEN: WILEY. ISSN 1878-0261

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Abstract

Oncogenesis of Ewing sarcoma (EwS), the second most common malignant bone tumor of childhood and adolescence, is dependent on the expression of chimeric EWSR1-ETS fusion oncogenes, most often EWSR1-FLI1 (E/F). E/F expression leads to dysregulation of focal adhesions (FAs) enhancing the migratory capacity of EwS cells. Here, we show that, in EwS cell lines and tissue samples, focal adhesion kinase (FAK) is expressed and phosphorylated at Y397 in an E/F-dependent way involving Ezrin. Employing different EwS cell lines as in vitro models, we found that key malignant properties of E/F are mediated via substrate-independent autophosphorylation of FAK on Y397. This phosphorylation results in enhanced FA formation, Rho-dependent cell migration, and impaired caspase-3-mediated apoptosis in vitro. Conversely, treatment with the FAK inhibitor 15 (1,2,4,5-benzenetetraamine tetrahydrochloride (Y15) enhanced caspase-mediated apoptosis and EwS cell migration, independent from the respective EWSR1-ETS fusion type, mimicking an anoikis-like phenotype and paralleling the effects of FAK siRNA knockdown. Our findings were confirmed in vivo using an avian chorioallantoic membrane model and provide a first rationale for the therapeutic use of FAK inhibitors to impair metastatic dissemination of EwS.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Steinestel, Konrad UNSPECIFIED UNSPECIFIED UNSPECIFIED Trautmann, Marcel UNSPECIFIED orcid.org/0000-0002-5842-1196 UNSPECIFIED Jansen, Esther-Pia UNSPECIFIED UNSPECIFIED UNSPECIFIED Dirksen, Uta UNSPECIFIED UNSPECIFIED UNSPECIFIED Rehkaemper, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mikesch, Jan-Henrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerke, Julia S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Orth, Martin F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sannino, Giuseppina UNSPECIFIED UNSPECIFIED UNSPECIFIED Arteaga, Maria-Francisca UNSPECIFIED UNSPECIFIED UNSPECIFIED Rossig, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Wardelmann, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruenewald, Thomas G. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-124070
DOI:	10.1002/1878-0261.12610
Journal or Publication Title:	Mol. Oncol.
Volume:	14
Number:	2
Page Range:	S. 248 - 261
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1878-0261
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FUSION PROTEIN; FAK; DIFFERENTIATION; INHIBITION; GROWTH; GENE; TRANSCRIPTION; SURVIVAL; CANCER; MAPK Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12407