The Clinical and Cellular Landscape of DKK1 in Osteosarcoma
- 1Albert Einstein College of Medicine
Abstract
Background: Dickkopf-1 (DKK1) is a secreted protein that acts as a Wnt antagonist and is implicated in osteosarcoma progression. Elevated circulating DKK1 levels have been described at OS diagnosis, but its circulating dynamics, prognostic relevance, and cellular distribution remain incompletely characterized. Methods: We analysed longitudinal plasma DKK1 in 34 patients using mixed-effects models, evaluated DKK1 expression and survival in two independent transcriptomic cohorts, and examined cellular and tissue distribution using single-cell transcriptomics and immunohistochemistry. Cultured mesenchymal stem cells were assessed as potential nonmalignant sources. Results: Circulating DKK1 declined by 12.4% per 30-day period during treatment, without significant changes detected around primary tumour resection or relapse. Metastatic presentation and poor histologic response were associated with higher estimated DKK1 levels. Higher tumour DKK1 expression was associated with worse overall and metastasis-free survival (pooled HRs per SD increase: 1.35 [95% CI 1.02 - 1.78] and 1.48 [1.06 - 2.07], respectively). DKK1 transcripts were predominantly detected in malignant cells across multiple subpopulations and protein staining was enriched in osteoid and matrix-rich regions of primary tumours. Conclusions: Tumour DKK1 expression is associated with adverse outcomes, while circulating concentration decline over treatment time. These findings support further prognostic evaluation and investigation of the associations among DKK1 expression and production, tissue localisation, and circulating levels.
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BibTeX
@misc{ariasstella2026clinical,
title = {{The Clinical and Cellular Landscape of DKK1 in Osteosarcoma}},
author = {E. Uceda Arias-Stella and L. Kastner and N. Copperman and G. Then and J. Karlin and A. Mahant and J. Crimella and M. Isakoff and M. Hayashi and M. R. Ewart and R. San Martin and A. Berg and C. A. Gregory and D. Loeb},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.26367177},
url = {https://www.medrxiv.org/content/10.64898/2026.11.03.26367177v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - The Clinical and Cellular Landscape of DKK1 in Osteosarcoma
AU - E. Uceda Arias-Stella
AU - L. Kastner
AU - N. Copperman
AU - G. Then
AU - J. Karlin
AU - A. Mahant
AU - J. Crimella
AU - M. Isakoff
AU - M. Hayashi
AU - M. R. Ewart
AU - R. San Martin
AU - A. Berg
AU - C. A. Gregory
AU - D. Loeb
PY - 2026
DA - 2026/11/03
PB - medRxiv
DO - 10.64898/2026.11.03.26367177
UR - https://www.medrxiv.org/content/10.64898/2026.11.03.26367177v1
AB - Background: Dickkopf-1 (DKK1) is a secreted protein that acts as a Wnt antagonist and is implicated in osteosarcoma progression. Elevated circulating DKK1 levels have been described at OS diagnosis, but its circulating dynamics, prognostic relevance, and cellular distribution remain incompletely characterized. Methods: We analysed longitudinal plasma DKK1 in 34 patients using mixed-effects models, evaluated DKK1 expression and survival in two independent transcriptomic cohorts, and examined cellular and tissue distribution using single-cell transcriptomics and immunohistochemistry. Cultured mesenchymal stem cells were assessed as potential nonmalignant sources. Results: Circulating DKK1 declined by 12.4% per 30-day period during treatment, without significant changes detected around primary tumour resection or relapse. Metastatic presentation and poor histologic response were associated with higher estimated DKK1 levels. Higher tumour DKK1 expression was associated with worse overall and metastasis-free survival (pooled HRs per SD increase: 1.35 [95% CI 1.02 - 1.78] and 1.48 [1.06 - 2.07], respectively). DKK1 transcripts were predominantly detected in malignant cells across multiple subpopulations and protein staining was enriched in osteoid and matrix-rich regions of primary tumours. Conclusions: Tumour DKK1 expression is associated with adverse outcomes, while circulating concentration decline over treatment time. These findings support further prognostic evaluation and investigation of the associations among DKK1 expression and production, tissue localisation, and circulating levels.
ER -