Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model
- Tulotta, C., Stefanescu, C., Beletkaia, E., Bussmann, J., Tarbashevich, K., Schmidt, T., Snaar-Jagalska, B.E.
- Disease models & mechanisms 9(2): 141-53 (Journal)
- Registered Authors
- Bussmann, Jeroen, Snaar-Jagalska, Ewa B., Tarbashevich, Katsiyarina
- CXCR4, CXCL12, IT1t, Triple-negative breast cancer, Metastases, Inter-species crosstalk, Xenograft, Zebrafish
- MeSH Terms
- Amino Acid Sequence
- Disease Models, Animal*
- Molecular Sequence Data
- Neoplasm Metastasis*
- Receptors, CXCR4/chemistry
- Receptors, CXCR4/metabolism*
- Sequence Homology, Amino Acid
- Triple Negative Breast Neoplasms/pathology*
- 26744352 Full text @ Dis. Model. Mech.
Tulotta, C., Stefanescu, C., Beletkaia, E., Bussmann, J., Tarbashevich, K., Schmidt, T., Snaar-Jagalska, B.E. (2016) Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model. Disease models & mechanisms. 9(2):141-53.
Triple negative breast cancer (TNBC) is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes including breast cancer metastases. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in TNBC early metastasis formation, we used the zebrafish xenograft model. Importantly, we demonstrate that cross communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes