Navi Hewage

Introduction: Breast cancer is the most common form of cancer and the leading cause of cancer death among women^1,2. Breast cancer prognosis is complex and patient-specific, involving the presence or absence of molecular targets within the tumor or tumor microenvironment (TME) ³. The TME is the ecosystem directly surrounding tumor cells, consisting of functionally different cells including immune cells, stromal cells, cytokines, and extracellular matrix components^1,3. Signaling processes such as chemokine secretions mediate interactions between the tumor and TME, providing the TME with roles in tumor growth, malignant transformation, self-renewal, immunosuppression, and metastasis¹. The CXCL12/CXCR4 chemokine axis directly correlates with poor prognosis and decreased survival among breast cancer patients¹. However, mechanisms of overexpression and the role of CXCL12/CXCR4 Axis is largely unknown^2,5,7. This study identifies processes of breast cancer progression involving CXCL12/CXCR4 and addresses its potential as a therapeutic target.  Methods: Transgenic mice harboring triple-negative breast cancer xenographs were treated with CXCR4 monoclonal antibody to study CXCL12/CXCR4 involvement in tumor growth⁵. Pharmacological inhibition of CXCR4 was demonstrated using Plerixafor (AMD3100), injected into mice expressing αSMA+, a marker of cancer-associated fibroblasts of the extracellular matrix². CXCL12/CXCR axis in epithelial-mesenchymal transition (EMT) of tumor cells was investigated by suppression of CXCL12-specific proteolytic glycoprotein (DPP)-4 with antagonist KR62436 (KR)⁴. Transmembrane protein LRP6 and CXCR4 relationship was determined via co-transfection in mice⁷. Finally, metastatic capacities of CXCL12 isoforms (α, β, and γ) were assessed by co-implanting CXCR4 breast cancer cells with human mammary fibroblasts in mice³.  Results: Mice treated with CXCR4 monoclonal antibody showed reduced tumor growth compared to controls, suggesting CXCR4 involvement⁵. Inhibition of CXCL12/CXCR4 with Plexarifor resulted in a significant response to immune checkpoint blockers and reduced several markers of desmoplasia, including TGFb, Ctgf, and Edn1². Mice treated with KR showed CXCL12/CXCR4 activation, resulting in increased tumor growth compared to controls⁴. Recombinant LRP6N was found to competitively inhibit CXCL12 binding to CXCR4, preventing CXCL12/CXCR4-induced breast cancer metastasis⁷. CXCR4-containing tumor-associated fibroblasts secreting CXCL12-γ showed higher levels of angiogenesis and metastasis, and reduced apoptosis than other isoforms³.  Conclusions: The CXCL12/CXCR4 Axis has shown to enhance tumor metastasis, fibrosis, immunosuppression and angiogenesis². CXCR4 modulation may contribute to congoing efforts in cancer therapy and provide a precision medicine approach based on expression status. This will allow selection of patients likely to be responsive to treatment, and fewer off-target effects^2,7. Further knowledge surrounding signaling mechanisms of this axis can advance understanding of its role in breast cancer.

1. Wagner, J., Rapsomaniki, M. A., Chevrier, S., Anzeneder, T., Langwieder, C., Dykgers, A., … Bodenmiller, B. (2019). A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer. Cell, 177(5). doi: 10.1016/j.cell.2019.03.005
2. Chen IX, Chauhan VP, Posada J, et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proceedings of the National Academy of Sciences. 2019;116(10):4558-4566. doi:10.1073/pnas.1815515116
3. Ray P, Stacer AC, Fenner J, et al. CXCL12-γ in primary tumors drives breast cancer metastasis. Oncogene. 2014;34(16):2043-2051. doi:10.1038/onc.2014.157
4. Yang F, Takagaki Y, Yoshitomi Y, et al. Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis. Cancer Research. 2018;79(4):735-746. doi:10.1158/0008-5472.can-18-0620
5. Azad BB, Chatterjee S, Lesniak WG, et al. A fully human CXCR4 antibody demonstrates diagnostic utility and therapeutic efficacy in solid tumor xenografts. Oncotarget. 2016;7(11). doi:10.18632/oncotarget.7111
6. Pernas S, Martin M, Kaufman PA, et al. Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial. The Lancet Oncology. 2018;19(6):812-824. doi:10.1016/s1470-2045(18)30147-5
7. Zhang J, Chen J, Wo D, et al. LRP6 Ectodomain Prevents SDF-1/CXCR4-Induced Breast Cancer Metastasis to Lung. Clinical Cancer Research. 2019;25(15):4832-4845. doi:10.1158/1078-0432.ccr-18-3557