Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer
Abstract Background 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 brea...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13058-018-1079-7 |
| _version_ | 1818603723358732288 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Abdi Ghaffari |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-12-16T13:27:42Z |
| format | Article |
| id | doaj.art-e01c03168cbb4202a2274dbf9828911d |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-16T13:27:42Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-e01c03168cbb4202a2274dbf9828911d2022-12-21T22:30:10ZengBMCBreast Cancer Research1465-542X2019-01-0121111110.1186/s13058-018-1079-7Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancerAbdi Ghaffari0Victoria Hoskin1Gulisa Turashvili2Sonal Varma3Jeff Mewburn4Graeme Mullins5Peter A. Greer6Friedemann Kiefer7Andrew G. Day8Yolanda Madarnas9Sandip SenGupta10Bruce E. Elliott11Department of Pathology and Molecular Medicine, Queen’s UniversityDepartment of Pathology and Molecular Medicine, Queen’s UniversityDepartment of Pathology and Molecular Medicine, Queen’s UniversityDepartment of Pathology and Molecular Medicine, Queen’s UniversityCancer Research Institute, Division of Cancer Biology and Genetics, Queen’s UniversityDepartment of Pathology and Molecular Medicine, Queen’s UniversityDepartment of Pathology and Molecular Medicine, Queen’s UniversityMax Planck Institute for Molecular BiomedicineKingston General Hospital Research InstituteDepartment of Oncology, Queen’s UniversityDepartment of Pathology and Molecular Medicine, Queen’s UniversityDepartment of Pathology and Molecular Medicine, Queen’s UniversityAbstract Background 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. Methods 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. Results 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. Conclusions 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.http://link.springer.com/article/10.1186/s13058-018-1079-7EzrinQuantitative intravital imagingCell migrationLymph node metastasisBiomarkerMetastatic disease |
| spellingShingle | 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 Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer Breast Cancer Research Ezrin Quantitative intravital imaging Cell migration Lymph node metastasis Biomarker Metastatic disease |
| title | Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer |
| title_full | Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer |
| title_fullStr | Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer |
| title_full_unstemmed | Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer |
| title_short | Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer |
| title_sort | intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer |
| topic | Ezrin Quantitative intravital imaging Cell migration Lymph node metastasis Biomarker Metastatic disease |
| url | http://link.springer.com/article/10.1186/s13058-018-1079-7 |
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