title: Receptor tyrosine kinase gene expression profiles of Ewing sarcomas reveal ROR1 as a potential therapeutic target in metastatic disease.
abstract: Receptor tyrosine kinases (RTKs) have provided molecular targets for the development of novel, prognosis-improving agents in many cancers; however, resistances to these therapies occur. On the cellular level, one resistance mechanism is attributed to functional RTK redundancies and compensatory cross-signaling, leading to perception of RTKs as signaling and target networks. To provide a basis for better exploitation of this network in Ewing sarcoma, we generated comprehensive qPCR gene expression profiles of RTKs in Ewing sarcoma cell lines and 21 untreated primary tumors. Key findings confirm broad-spectrum RTK expressions with potential for signaling redundancy. Profile analyses with regard to patient risk-group further revealed several individual RTKs of interest. Among them, VEGFR3 and TIE1 showed high-level expressions and also were suggestive of poor prognosis in localized tumors; underscoring the relevance of angiogenic signaling pathways and tumor-stroma interactions in Ewing sarcoma. Of note, compared to localized disease, tumors derived from metastatic disease were marked by global high-level RTK expressions. Nine individual RTKs were significantly over-expressed, suggesting contributions to molecular mechanisms of metastasis. Of these, ROR1 is being pursued as therapeutic target in leukemias and carcinomas, but un-characterized in sarcomas. We demonstrate expression of ROR1 and its putative ligand Wnt5a in Ewing sarcomas, and of an active ROR1 protein variant in cell lines. ROR1 silencing impaired cell migration in vitro. Therefore, ROR1 calls for further evaluation as a therapeutic target in metastatic Ewing sarcoma; and described as a pseudo-kinase with several isoforms, underlines these additional complexities arising in our understanding of RTK signaling networks.
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany. Electronic address: Jenny.Potratz@ukmuenster.de.
authors.forename: Jenny
authors.initials: J
authors.lastname: Potratz
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Tillmanns
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Berning
authors.affiliation: Institute of Bioinformatics, Westfälische-Wilhelms Universität Münster, Niels-Stensen-Strasse 12, 48149 Münster, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Korsching
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Schaefer
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Lechtape
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schleithoff
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Unland
authors.affiliation: Institute of Pathology, University Medical Center Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Karl-Ludwig
authors.initials: KL
authors.lastname: Schäfer
authors.affiliation: Department of Inner Medicine IV, Hematology and Oncology, University Hospital Halle, Ernst-Grube-Strasse 40, 06120 Halle (Saale), Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Jürgens
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Dirksen
mesh_terms: D000293:Adolescent; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use; D000067492:RNAi Therapeutics; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000032:analysis / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D059467:Transcriptome; D000071818:Wnt-5a Protein / Q000032:analysis
chemical_list: D034741:RNA, Small Interfering; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors
keywords: Ewing sarcoma; Metastasis; ROR1; Receptor tyrosine kinase; Therapeutic target