title: SRC inhibition represents a potential therapeutic strategy in liposarcoma.
abstract: Liposarcomas (LS) are the most common malignant mesenchymal tumors, with an overall long-term mortality rate of 60%. LS comprise three major subtypes, i.e., well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS), myxoid/round cell liposarcoma (MLS) and pleomorphic liposarcoma (PLS). Aiming at the preclinical identification of novel therapeutic options, we here investigate the functional significance of SRC in primary human LS and in LS-derived cell lines. Immunohistochemical and Western blot analyses reveal relevant levels of activated p-(Tyr416)-SRC in LS of the different subtypes with particular activation in MLS and PLS. Dysregulation of the SRC modifiers CSK and PTP1B was excluded as major reason for the activation of the kinase. Consistent siRNA-mediated knockdown of SRC or inhibition by the SRC inhibitor Dasatinib led to decreased proliferation of LS cell lines of the different subtypes, with MLS cells reacting particularly sensitive in MTT assays. Flow cytometric analyses revealed that this effect was due to a significant decrease in mitotic activity and an induction of apoptosis. SRC inhibition by Dasatinib resulted in dephosphorylation of SRC itself, its interacting partners FAK and IGF-IR as well as its downstream target AKT. Consistent with a particular role of SRC in cell motility, Dasatinib reduced the migratory and invasive potential of MLS cells in Boyden chamber and Matrigel chamber assays. In summary, we provide evidence that SRC activation plays an important role in LS biology and therefore represents a potential therapeutic target, particularly in MLS and PLS.
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.|Department of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sievers
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.|Department of Pathology, University Hospital Muenster, Muenster, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Trautmann
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kindler
authors.affiliation: Department of Pathology, University Hospital Muenster, Muenster, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Huss
authors.affiliation: Department of Pathology, University Hospital Muenster, Muenster, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Gruenewald
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Muenster, Muenster, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Dirksen
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Renner
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Mechtersheimer
authors.affiliation: Laboratory of Solid Tumors Genetics, Nice University Hospital, Nice, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pedeutour
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Pierre
authors.initials: P
authors.lastname: Åman
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nishio
authors.affiliation: Department of Pathology, University Hospital Goettingen, Goettingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
authors.affiliation: Department of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.|Department of Pathology, University Hospital Muenster, Muenster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.|Department of Pathology, University Hospital Muenster, Muenster, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D008080:Liposarcoma / Q000188:drug therapy*; D018208:Liposarcoma, Myxoid / Q000188:drug therapy*; D008938:Mitosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000597236:IGF1R protein, human; D047428:Protein Kinase Inhibitors; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1; D000081247:CSK Tyrosine-Protein Kinase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; C000631346:CSK protein, human; D051057:Proto-Oncogene Proteins c-akt; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Dasatinib; SRC; liposarcoma; siRNA