American Association for Cancer Research
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Supplemental Table S1. Wnt target genes from Activation of Wnt/β-Catenin in Ewing Sarcoma Cells Antagonizes EWS/ETS Function and Promotes Phenotypic Transition to More Metastatic Cell States

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posted on 2023-03-31, 00:31 authored by Elisabeth A. Pedersen, Rajasree Menon, Kelly M. Bailey, Dafydd G. Thomas, Raelene A. Van Noord, Jenny Tran, Hongwei Wang, Ping Ping Qu, Antje Hoering, Eric R. Fearon, Rashmi Chugh, Elizabeth R. Lawlor

Supplemental table S1. RNA-seq differentially expressed genes modulated by Wnt3a (Table S1A) or Wnt3a+RSPO2 (Table S1B).

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NIH

Alex's Lemonade Stand Foundation

University of Michigan

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ARTICLE ABSTRACT

Ewing sarcomas are characterized by the presence of EWS/ETS fusion genes in the absence of other recurrent genetic alterations and mechanisms of tumor heterogeneity that contribute to disease progression remain unclear. Mutations in the Wnt/β-catenin pathway are rare in Ewing sarcoma but the Wnt pathway modulator LGR5 is often highly expressed, suggesting a potential role for the axis in tumor pathogenesis. We evaluated β-catenin and LGR5 expression in Ewing sarcoma cell lines and tumors and noted marked intra- and inter-tumor heterogeneity. Tumors with evidence of active Wnt/β-catenin signaling were associated with increased incidence of tumor relapse and worse overall survival. Paradoxically, RNA sequencing revealed a marked antagonism of EWS/ETS transcriptional activity in Wnt/β-catenin–activated tumor cells. Consistent with this, Wnt/β-catenin–activated cells displayed a phenotype that was reminiscent of Ewing sarcoma cells with partial EWS/ETS loss of function. Specifically, activation of Wnt/β-catenin induced alterations to the actin cytoskeleton, acquisition of a migratory phenotype, and upregulation of EWS/ETS–repressed genes. Notably, activation of Wnt/β-catenin signaling led to marked induction of tenascin C (TNC), an established promoter of cancer metastasis, and an EWS/ETS–repressed target gene. Loss of TNC function in Ewing sarcoma cells profoundly inhibited their migratory and metastatic potential. Our studies reveal that heterogeneous activation of Wnt/β-catenin signaling in subpopulations of tumor cells contributes to phenotypic heterogeneity and disease progression in Ewing sarcoma. Significantly, this is mediated, at least in part, by inhibition of EWS/ETS fusion protein function that results in derepression of metastasis-associated gene programs. Cancer Res; 76(17); 5040–53. ©2016 AACR.

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