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Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer.

Breast cancer research : BCR (2019-01-27)
Abdi Ghaffari, Victoria Hoskin, Gulisa Turashvili, Sonal Varma, Jeff Mewburn, Graeme Mullins, Peter A Greer, Friedemann Kiefer, Andrew G Day, Yolanda Madarnas, Sandip SenGupta, Bruce E Elliott
RESUMEN

Limited understanding of the cancer biology of metastatic sites is a major factor contributing to poor outcomes in cancer patients. The regional lymph nodes are the most common site of metastasis in most solid cancers and their involvement is a strong predictor of relapse in breast cancer (BC). We have previously shown that ezrin, a cytoskeletal-membrane linker protein, is associated with lymphovascular invasion and promotes metastatic progression in BC. However, the efficacy of pharmacological inhibition of ezrin in blocking cancer cell migration and metastasis remains unexplored in BC. We quantified ezrin expression in a BC tissue microarray (n = 347) to assess its correlation with risk of relapse. Next, we developed a quantitative intravital microscopy (qIVM) approach, using a syngeneic lymphatic reporter mouse tumor model, to investigate the effect of systemic ezrin inhibition on cancer cell migration and metastasis. We show that ezrin is expressed at significantly higher levels in lymph node metastases compared to matched primary tumors, and that a high tumor ezrin level is associated with increased risk of relapse in BC patients with regional disease. Using qIVM, we observe a subset of cancer cells that retain their invasive and migratory phenotype at the tumor-draining lymph node. We further show that systemic inhibition of ezrin, using a small molecule compound (NSC668394), impedes the migration of cancer cells in vivo. Furthermore, systemic ezrin inhibition leads to reductions in metastatic burden at the distal axillary lymph node and lungs. Our findings demonstrate that the tumor ezrin level act as an independent biomarker in predicting relapse and provide a rationale for therapeutic targeting of ezrin to reduce the metastatic capacity of cancer cells in high-risk BC patients with elevated ezrin expression.

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Sigma-Aldrich
Anti-γ-Tubulin antibody, Mouse monoclonal, clone GTU-88, purified from hybridoma cell culture
Sigma-Aldrich
Monoclonal Anti-Ezrin antibody produced in mouse, clone 3C12, ascites fluid
Sigma-Aldrich
Anti-LYVE1 Antibody, from rabbit, purified by affinity chromatography