Abstract
Tumor heterogeneity is a major impediment to cancer cures. Tumor cell heterogeneity can arise by irreversible genetic mutation, as well as by non-mutational mechanisms, which can be reversibly modulated by the tumor microenvironment and the epigenome. We recently reported that the chemokine receptor CXCR4 is induced in Ewing sarcoma cells in response to microenvironmental stress. In the current study, we investigated plasticity of CXCR4 expression in vivo and assessed whether CXCR4 impacts on tumor growth. Our studies showed that Ewing sarcoma cells convert between CXCR4 negative and CXCR4 positive states in vivo and that positive cells are most abundant adjacent to areas of necrosis. In addition, tumor volumes directly correlated with CXCR4 expression supporting a role for CXCR4 in growth promotion. Mechanistically, our results show that, in ambient conditions where CXCR4 expression is low, the CXCR4 promoter exists in a poised, bivalent state with simultaneous enrichment of both activating (H3K4me3) and repressive (H3K27me3) post-translational histone modifications. In contrast, when exposed to stress, CXCR4 negative cells lose the H3K27me3 mark. This loss of promoter bivalency is associated with CXCR4 upregulation. These studies demonstrate that stress-dependent plasticity of CXCR4 is, in part, mediated by epigenetic plasticity and a bivalent promoter.
Highlights
Tumor heterogeneity contributes to tumor progression and remains a major challenge in the treatment and diagnosis of cancer as well as for the development of novel cancer therapeutics [1, 2]
CXCR4 negative/CD99 positive tumor cells were present in abundance in tumors that arose from CXCR4 positive cells (Figure 2A)
Given the integral role of epigenetic deregulation in Ewing sarcoma pathogenesis, and our observations that the transition of CXCR4 negative cells into CXCR4 positive states is associated with changes in levels of CXCR4 transcript, we investigated whether epigenetic plasticity contributes to stress-induced plasticity
Summary
Tumor heterogeneity contributes to tumor progression and remains a major challenge in the treatment and diagnosis of cancer as well as for the development of novel cancer therapeutics [1, 2]. Biological heterogeneity between tumor and non-tumor stroma is a major determinant of tumor behavior, it is increasingly evident that phenotypic heterogeneity among tumor cells themselves is of profound importance to disease progression, therapy response and clinical outcomes This phenotypic heterogeneity can include variability in gene expression, motility, and metastatic potential across cells in a tumor [3] and can be driven by both genetic and epigenetic mechanisms, as well as by contributions of the tumor microenvironment [2, 4]. Exposure of tumor cells to microenvironmental stress, including growth factor deprivation, hypoxia, and physical growth constraints resulted in upregulation of CXCR4, either at the level of mRNA or cell surface protein expression, or both [9] This www.impactjournals.com/oncotarget upregulation of CXCR4 was associated with phenotypic transition of Ewing sarcoma cells from relatively nonmotile states to cells that actively migrated and invaded towards the CXCL12 ligand [9]. Elucidation of the mechanisms underlying CXCR4 regulation in Ewing sarcoma could provide insights into the molecular mechanisms of Ewing sarcoma cell heterogeneity and tumor progression
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