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Peer-reviewedCC BY 4.0Journal of Bone Oncology

Influence of the Dickkopf-related protein 1-(co)receptor axis on early bone colonization in a subcutaneous human prostate cancer xenograft model

  • By Marie-Therese Haider1,2
  • Vera Freytag2
  • Anke Baranowsky3
  • Farbod Bahreini1
  • Christof Niehrs4,5
  • Thorsten Schinke6
  • Michael Amling6
  • Tobias Lange1,2
6 affiliations
  1. 1Institute of Anatomy, University of Luebeck, Luebeck, Germany
  2. 2Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  3. 3Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  4. 4Institute of Molecular Biology (IMB), Mainz, Germany
  5. 5Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany
  6. 6Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Abstract

Background: The Wnt signaling pathway drives tumor cell invasion, metastasis, and bone formation, making it a key mediator of prostate cancer (PCa) skeletal metastasis. Dickkopf-related protein 1 (DKK1) inhibits canonical Wnt signaling by binding to the Wnt co-receptor LRP5/6; the DKK1-binding receptors Kremen1/2 cooperate in this inhibition. We investigated whether targeting this axis affects early bone colonization in a subcutaneous PCa xenograft model, an approach that reflects spontaneous metastatic dissemination but is limited by low metastatic frequency and the requirement for immunodeficient hosts.

Methods: Luc2/RGB-labelled PC-3 cells were implanted subcutaneously into male immunodeficient mice. DKK1 was neutralized with the humanized anti-DKK1 monoclonal antibody hDKN-01 during primary tumor growth (pre-OP) or following primary tumor surgical resection (post-OP). Further experiments used host mice with heterozygous Lrp5 gain-of-function mutation (Lrp5+/G170V) or knockout of Kremen1 (Krm1−/−), Kremen2 (Krm2−/−), or both. Bone metastatic burden was quantified using anti-luciferase immunohistochemistry on serial hindlimb sections. Serum DKK1 ELISA and bone histomorphometry confirmed treatment efficacy and genotype phenotypes.

Results: hDKN-01 reduced serum DKK1 and increased trabecular bone volume, confirming biological activity, but did not affect tumor growth or bone metastatic burden in either treatment window. Lrp5+/G170V and Krm1/Krm2 double-KO mice showed expected bone phenotypes without altered bone colonization (detected in 13–33% of mice). Notably, Krm2−/− mice showed only single disseminated tumor cells in bone, with no outgrowing colonies (0% of mice).

Conclusions: Neither systemic neutralization of DKK1 nor Lrp5 mutation nor Krm1 or Krm1/Krm2 knockout had any effect on bone colonization of subcutaneous PC-3 xenografts in immunodeficient mice. In contrast, Krm2 knockout prevented the formation of colonizing bone metastases, apparently depending on the presence of Krm1.

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Cite

BibTeXRIS
BibTeX
@article{haider2026influence,
  title = {{Influence of the Dickkopf-related protein 1-(co)receptor axis on early bone colonization in a subcutaneous human prostate cancer xenograft model}},
  author = {By Marie-Therese Haider and Vera Freytag and Anke Baranowsky and Farbod Bahreini and Christof Niehrs and Thorsten Schinke and Michael Amling and Tobias Lange},
  journal = {Journal of Bone Oncology},
  year = {2026},
  month = oct,
  doi = {10.1016/j.jbo.2026.100814},
  url = {https://doi.org/10.1016/j.jbo.2026.100814},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Influence of the Dickkopf-related protein 1-(co)receptor axis on early bone colonization in a subcutaneous human prostate cancer xenograft model
AU  - By Marie-Therese Haider
AU  - Vera Freytag
AU  - Anke Baranowsky
AU  - Farbod Bahreini
AU  - Christof Niehrs
AU  - Thorsten Schinke
AU  - Michael Amling
AU  - Tobias Lange
PY  - 2026
DA  - 2026/10/30
JO  - Journal of Bone Oncology
DO  - 10.1016/j.jbo.2026.100814
UR  - https://doi.org/10.1016/j.jbo.2026.100814
AB  - Background: The Wnt signaling pathway drives tumor cell invasion, metastasis, and bone formation, making it a key mediator of prostate cancer (PCa) skeletal metastasis. Dickkopf-related protein 1 (DKK1) inhibits canonical Wnt signaling by binding to the Wnt co-receptor LRP5/6; the DKK1-binding receptors Kremen1/2 cooperate in this inhibition. We investigated whether targeting this axis affects early bone colonization in a subcutaneous PCa xenograft model, an approach that reflects spontaneous metastatic dissemination but is limited by low metastatic frequency and the requirement for immunodeficient hosts.  Methods: Luc2/RGB-labelled PC-3 cells were implanted subcutaneously into male immunodeficient mice. DKK1 was neutralized with the humanized anti-DKK1 monoclonal antibody hDKN-01 during primary tumor growth (pre-OP) or following primary tumor surgical resection (post-OP). Further experiments used host mice with heterozygous Lrp5 gain-of-function mutation (Lrp5+/G170V) or knockout of Kremen1 (Krm1−/−), Kremen2 (Krm2−/−), or both. Bone metastatic burden was quantified using anti-luciferase immunohistochemistry on serial hindlimb sections. Serum DKK1 ELISA and bone histomorphometry confirmed treatment efficacy and genotype phenotypes.  Results: hDKN-01 reduced serum DKK1 and increased trabecular bone volume, confirming biological activity, but did not affect tumor growth or bone metastatic burden in either treatment window. Lrp5+/G170V and Krm1/Krm2 double-KO mice showed expected bone phenotypes without altered bone colonization (detected in 13–33% of mice). Notably, Krm2−/− mice showed only single disseminated tumor cells in bone, with no outgrowing colonies (0% of mice).  Conclusions: Neither systemic neutralization of DKK1 nor Lrp5 mutation nor Krm1 or Krm1/Krm2 knockout had any effect on bone colonization of subcutaneous PC-3 xenografts in immunodeficient mice. In contrast, Krm2 knockout prevented the formation of colonizing bone metastases, apparently depending on the presence of Krm1.
SN  - 2212-1366
SN  - 2212-1374
ER  -