Pedersen Elisabeth A, Menon Rajasree, Bailey Kelly M, Thomas Dafydd G, Van Noord Raelene A, Tran Jenny, Wang Hongwei, Qu Ping Ping, Hoering Antje, Fearon Eric R, Chugh Rashmi, Lawlor Elizabeth R
Translational Oncology Program, The University of Michigan, Ann Arbor, Michigan. Department of Pathology, The University of Michigan, Ann Arbor, Michigan.
Department of Computational Medicine & Bioinformatics, The University of Michigan, Ann Arbor, Michigan.
Cancer Res. 2016 Sep 1;76(17):5040-53. doi: 10.1158/0008-5472.CAN-15-3422. Epub 2016 Jun 30.
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.
尤因肉瘤的特征是存在EWS/ETS融合基因，且不存在其他复发性基因改变，而导致疾病进展的肿瘤异质性机制仍不清楚。Wnt/β-连环蛋白通路中的突变在尤因肉瘤中很少见，但Wnt通路调节剂LGR5通常高表达，提示该轴在肿瘤发病机制中可能发挥作用。我们评估了尤因肉瘤细胞系和肿瘤中β-连环蛋白和LGR5的表达，发现肿瘤内和肿瘤间存在明显的异质性。有活跃Wnt/β-连环蛋白信号传导证据的肿瘤与肿瘤复发率增加和总体生存率较差相关。矛盾的是，RNA测序显示在Wnt/β-连环蛋白激活的肿瘤细胞中EWS/ETS转录活性受到明显拮抗。与此一致，Wnt/β-连环蛋白激活的细胞表现出一种类似于部分EWS/ETS功能丧失的尤因肉瘤细胞的表型。具体而言，Wnt/β-连环蛋白的激活诱导了肌动蛋白细胞骨架的改变、迁移表型的获得以及EWS/ETS抑制基因的上调。值得注意的是，Wnt/β-连环蛋白信号传导的激活导致腱生蛋白C（TNC）显著诱导，TNC是一种已确定的癌症转移促进因子，也是一个EWS/ETS抑制的靶基因。尤因肉瘤细胞中TNC功能的丧失深刻抑制了它们的迁移和转移潜能。我们的研究表明，肿瘤细胞亚群中Wnt/β-连环蛋白信号传导的异质性激活导致了尤因肉瘤的表型异质性和疾病进展。重要的是，这至少部分是由EWS/ETS融合蛋白功能的抑制介导的，该抑制导致与转移相关的基因程序去抑制。《癌症研究》；76(17)；5040 - 53。©2016美国癌症研究协会。
