2. Academic Validation
  3. 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

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

  • Dis Model Mech. 2016 Feb;9(2):141-53. doi: 10.1242/dmm.023275.
Claudia Tulotta 1,  Cristina Stefanescu 1,  Elena Beletkaia 2,  Jeroen Bussmann 3,  Katsiaryna Tarbashevich 4,  Thomas Schmidt 2,  B Ewa Snaar-Jagalska 5
Affiliations

Affiliations

  • 1 Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
  • 2 Physics of Life Processes, Kamerligh Onnes-Huygens Laboratory, Leiden University, Niels Bohrweg 2, Leiden 2333 CA, The Netherlands.
  • 3 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.
  • 4 Institute for Cell Biology, ZMBE, Von-Esmarch-Str 56, Muenster 48149, Germany.
  • 5 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.
PMID: 26744352 DOI: 10.1242/dmm.023275
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.

Keywords

CXCL12; CXCR4; IT1t; Inter-species crosstalk; Metastases; Triple-negative breast cancer; Xenograft; Zebrafish.

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