Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma

Aashi Chaturvedi, Laura M. Hoffman, Christopher C. Jensen, Yi Chun Lin, Allie H. Grossmann, R Randall, Stephen L. Lessnick, Alana L. Welm, Mary C. Beckerle

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2695-2709
Number of pages15
JournalMolecular Biology of the Cell
Volume25
Issue number18
DOIs
StatePublished - Sep 15 2014
Externally publishedYes

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Ewing's Sarcoma
Zyxin
Cell Adhesion
Dissection
Actins
Integrins
Genes
Bone Neoplasms
Genetic Translocation
Focal Adhesions
Oncogenes
Heterografts
Extracellular Matrix
Neoplasms
Transcription Factors
Lung
Growth
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma. / Chaturvedi, Aashi; Hoffman, Laura M.; Jensen, Christopher C.; Lin, Yi Chun; Grossmann, Allie H.; Randall, R; Lessnick, Stephen L.; Welm, Alana L.; Beckerle, Mary C.

In: Molecular Biology of the Cell, Vol. 25, No. 18, 15.09.2014, p. 2695-2709.

Research output: Contribution to journalArticle

Chaturvedi, Aashi ; Hoffman, Laura M. ; Jensen, Christopher C. ; Lin, Yi Chun ; Grossmann, Allie H. ; Randall, R ; Lessnick, Stephen L. ; Welm, Alana L. ; Beckerle, Mary C. / Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma. In: Molecular Biology of the Cell. 2014 ; Vol. 25, No. 18. pp. 2695-2709.
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