Abstract IA26: Cell plasticity and metastatic progression of Ewing sarcoma

Tumor heterogeneity contributes to tumor relapse and metastasis and is a major impediment to cancer cures. Sources of tumor heterogeneity are diverse and include the contributions of tumor cells, nontumor cells, and the extracellular matrix (ECM). Tumor cell heterogeneity can arise by irreversible genetic mutation, as well as by nonmutational mechanisms, which can be reversibly modulated by changes in the epigenome and the tumor microenvironment. In carcinomas, such nonmutational tumor cell plasticity plays a key role in metastatic progression. In particular, in response to cues from the microenvironment, aggressive carcinoma cells activate an epithelial-to-mesenchymal transition (EMT) program that results in transition of cells from proliferative to metastasis-initiating states. Bone and soft tissue sarcomas also frequently progress to lethal metastatic disease. However, unlike their epithelial counterparts, sarcoma cells are mesenchymal by nature and the contribution of cell plasticity to sarcoma metastasis remains to be fully elucidated. We have discovered that Ewing sarcoma, a highly metastatic tumor with peak incidence in adolescents and young adults, is profoundly plastic. When Ewing sarcoma cells are exposed to hypoxia or deprived of growth factors---microenvironmental stresses that are encountered in vivo---they undergo phenotypic transitions from relatively nonmotile to highly migratory and invasive states. These transitions are associated with upregulation of CXCR4 and activation of Src and are, at least in part, epigenetically determined. In addition, we have shown that activation of the Wnt/beta-catenin pathway by exposure to canonical Wnt ligands induces similar phenotypic transitions in Wnt-responsive cells. Interestingly, these studies also showed that the impact of Wnt/beta-catenin activation on the Ewing sarcoma cell phenotype is in large part mediated by a seemingly paradoxical inhibition of the EWS/FLI1-dependent transcriptional signature. Significantly, recent studies from other groups have demonstrated heterogeneity of EWS/FLI1 expression among individual Ewing sarcoma cells in vitro and in vivo, and cells with reduced EWS/FLI1 levels have been shown to be more metastatic. Thus, these studies together implicate tumor cell heterogeneity and cell plasticity as key contributors to Ewing sarcoma invasion and metastasis. This talk will review the published data that support cell plasticity and cell state transitions as key drivers of Ewing sarcoma metastasis. In addition, new unpublished data will be presented in support of our hypothesis that Wnt/beta-catenin-activated Ewing sarcoma cells alter tumor:tumor microenvironment crosstalk to promote bone resorption and metastasis. Specifically, results of proteomics studies that define the secretome of Wnt-activated cells will be presented. The results of these studies show that Wnt/beta-catenin activated Ewing sarcoma cells secrete ECM proteins that contribute to matrix remodeling. Thus, heterogeneity and plasticity of Ewing sarcoma tumor cells in response to canonical Wnt ligands in the tumor microenvironment leads to changes in the ECM and these changes, in turn, induce changes in both the tumor cells and the tumor microenvironment that promote tumor metastasis. Citation Format: Elizabeth R. Lawlor. Cell plasticity and metastatic progression of Ewing sarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA26.