PUBLICATION

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

Authors
Tulotta, C., Stefanescu, C., Beletkaia, E., Bussmann, J., Tarbashevich, K., Schmidt, T., Snaar-Jagalska, B.E.
ID
ZDB-PUB-160109-5
Date
2016
Source
Disease models & mechanisms   9(2): 141-53 (Journal)
Registered Authors
Bussmann, Jeroen, Snaar-Jagalska, Ewa B., Tarbashevich, Katsiyarina
Keywords
CXCR4, CXCL12, IT1t, Triple-negative breast cancer, Metastases, Inter-species crosstalk, Xenograft, Zebrafish
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Disease Models, Animal*
  • Female
  • Heterografts
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Neoplasm Metastasis*
  • Receptors, CXCR4/chemistry
  • Receptors, CXCR4/metabolism*
  • Sequence Homology, Amino Acid
  • Triple Negative Breast Neoplasms/pathology*
  • Zebrafish
(all 14)
PubMed
26744352 Full text @ Dis. Model. Mech.
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 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
Figures
Figure Gallery (9 images)
Show all Figures
Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
cxcl12at30516/t30516standard conditionsProtruding-mouth
cxcr4bt26035/t26035standard conditionsProtruding-mouth
1 - 2 of 2
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gl22TgTransgenic Insertion
    mu100
      		Indel
      s843TgTransgenic Insertion
        t26035
          		Point Mutation
          t30516
            		Point Mutation
            ump2TgTransgenic Insertion
              1 - 6 of 6
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              Human Disease / Model
              Human Disease Fish Conditions Evidence
              triple-receptor negative breast cancerTAS
              1 - 1 of 1
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              Sequence Targeting Reagents
              No data available
              Fish
              Fish
              cxcl12at30516/t30516
              cxcr4bt26035/t26035
              1 - 2 of 2
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              Antibodies
              No data available
              Orthology
              Gene Orthology
              cxcl12a
              cxcl12b
              cxcr4a
              cxcr4b
              1 - 4 of 4
              Show
              Engineered Foreign Genes
              Marker Marker Type Name
              EGFPEFGEGFP
              mCherryEFGmCherry
              1 - 2 of 2
              Show
              Mapping
              No data available
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              Citation
              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.