The findings from these studies demonstrate that Ewing sarcoma cells transition between CXCR4 negative and CXCR4 positive states in vivo, that this phenotypic heterogeneity contributes to tumor growth and is, at least in part, driven by epigenetic plasticity of the CXCR4 promoter in response to microenvironmental stress. Here, CXCR4 is linked to Ewing sarcoma.