title: Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma.
abstract: Ewing sarcoma is the second-most-common bone cancer in children. Driven by an oncogenic chromosomal translocation that results in the expression of an aberrant transcription factor, EWS/FLI, the disease is typically aggressive and micrometastatic upon presentation. Silencing of EWS/FLI in patient-derived tumor cells results in the altered expression of hundreds to thousands of genes and is accompanied by dramatic morphological changes in cytoarchitecture and adhesion. Genes encoding focal adhesion, extracellular matrix, and actin regulatory proteins are dominant targets of EWS/FLI-mediated transcriptional repression. Reexpression of genes encoding just two of these proteins, zyxin and α5 integrin, is sufficient to restore cell adhesion and actin cytoskeletal integrity comparable to what is observed when the EWS/FLI oncogene expression is compromised. Using an orthotopic xenograft model, we show that EWS/FLI-induced repression of α5 integrin and zyxin expression promotes tumor progression by supporting anchorage-independent cell growth. This selective advantage is paired with a tradeoff in which metastatic lung colonization is compromised.
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.
authors: Aashi
authors: A
authors: Chaturvedi
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112 Department of Biology, University of Utah, Salt Lake City, UT 84112.
authors: Laura M
authors: LM
authors: Hoffman
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors: Christopher C
authors: CC
authors: Jensen
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.
authors: Yi-Chun
authors: YC
authors: Lin
authors: Department of Pathology, University of Utah, Salt Lake City, UT 84112.
authors: Allie H
authors: AH
authors: Grossmann
authors: Center for Children's Cancer Research, Huntsman Cancer Institute, Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, UT 84132 Department of Orthopaedics, Sarcoma Services, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors: R Lor
authors: RL
authors: Randall
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112 Center for Children's Cancer Research, Huntsman Cancer Institute, Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, UT 84132.
authors: Stephen L
authors: SL
authors: Lessnick
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.
authors: Alana L
authors: AL
authors: Welm
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112 Department of Biology, University of Utah, Salt Lake City, UT 84112 mary.beckerle@hci.utah.edu.
authors: Mary C
authors: MC
authors: Beckerle
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology; D060589:Zyxin / Q000378:metabolism
chemical_list: C106031:EWS-FLI fusion protein; D039564:Integrin alphaV; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; C092842:ZYX protein, human; D060589:Zyxin