title: 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.
abstract: 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 metastasis. 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 the formation of TNBC early metastases, 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.
authors.affiliation: Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tulotta
authors.affiliation: Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Cristina
authors.initials: C
authors.lastname: Stefanescu
authors.affiliation: Physics of Life Processes, Kamerligh Onnes-Huygens Laboratory, Leiden University, Niels Bohrweg 2, Leiden 2333 CA, The Netherlands.
authors.forename: Elena
authors.initials: E
authors.lastname: Beletkaia
authors.affiliation: Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bussmann
authors.affiliation: Institute for Cell Biology, ZMBE, Von-Esmarch-Str 56, Muenster 48149, Germany.
authors.forename: Katsiaryna
authors.initials: K
authors.lastname: Tarbashevich
authors.affiliation: Physics of Life Processes, Kamerligh Onnes-Huygens Laboratory, Leiden University, Niels Bohrweg 2, Leiden 2333 CA, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands B.E.Snaar-Jagalska@biology.leidenuniv.nl.
authors.forename: B Ewa
authors.initials: BE
authors.lastname: Snaar-Jagalska
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*; D015027:Zebrafish
chemical_list: C527276:CXCR4 protein, human; D008024:Ligands; D019718:Receptors, CXCR4
keywords: CXCL12; CXCR4; IT1t; Inter-species crosstalk; Metastases; Triple-negative breast cancer; Xenograft; Zebrafish