Abstract
Ezrin links the cytoskeleton to cell surface integrins and plasma membrane receptors, contributing to the proliferative and metastatic potential of cancer cells. Elevated ezrin expression in several cancers is associated with poor outcomes. Tumor cell ezrin expression and function have been investigated in depth; however, its role in macrophages and other tumor microenvironment cells remains unexplored. Macrophages profoundly influence tumorigenesis, and here we explore ezrin’s influence on tumor-promoting macrophage functions. Ezrin knockdown in THP-1 macrophages reveals its important contribution to adhesion to endothelial cells. Unexpectedly, ezrin is essential for the basal and breast cancer cell-stimulated THP-1 expression of ITGAM mRNA that encodes integrin CD11b, critical for cell adhesion. Ezrin skews the differentiation of THP-1 macrophages towards the pro-tumorigenic, M2 subtype, as shown by the reduced expression of FN1, IL10, and CCL22 mRNAs following ezrin knockdown. Additionally, macrophage ezrin contributes to the secretion of factors that stimulate tumor cell migration, invasion, and clonogenic growth. Lastly, THP-1 ezrin is critical for the expression of mRNAs encoding vascular endothelial growth factor (VEGF)-A and matrix metalloproteinase (MMP)-9, consistent with pro-tumorigenic function. Collectively, our results provide insight into ezrin’s role in tumorigenesis, revealing a bidirectional interaction between tumor-associated macrophages and tumor cells, and suggest myeloid cell ezrin as a target for therapeutic intervention against cancer.
Highlights
Ezrin is a member of the ezrin-radixin-moesin (ERM) family of cytoplasmic proteins whose primary function is connecting the plasma membrane to the underlying cortical actin cytoskeleton [1]
We investigated the specific role of myeloid cell ezrin in in vitro tumorigenic properties of macrophages, and in the reciprocal communication between these cells and breast cancer-derived cell lines (Figure 7; see Table S1 for summary of results)
We reveal a critical contribution of myeloid ezrin in endothelial cell interaction as the stable knockdown of ezrin in THP-1 cells abrogates binding to human umbilical vein cells (HUVECs) by about 75% (Figure 1A)
Summary
Ezrin is a member of the ezrin-radixin-moesin (ERM) family of cytoplasmic proteins whose primary function is connecting the plasma membrane to the underlying cortical actin cytoskeleton [1]. Ezrin shares substantial sequence similarity with other ERM proteins, i.e., moesin and radixin. Following stimulus-dependent binding of the FERM domain to plasma membrane PIP2, ezrin Thr567 phosphorylation unmasks the C-terminus to permit interaction with underlying F-actin [4]. Ezrin transduces extracellular signals by FERM domain interaction with trans-membrane proteins, including CD43, CD44, ICAM1, ICAM2, and EBP50 [5,6,7,8]. Ezrin contributes to breast cancer stem cell chemo-resistance, and has been proposed as a prognostic marker [15]. By stimulating the epithelial-to-mesenchymal transition, ezrin is thought to promote tumor metastasis in breast and osteosarcoma cancer cells [16,17]
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