Bone-derived DKK1 linked to progenitor-driven myelopoiesis in breast cancer

A study in Blood examined whether breast cancer durably reprograms hematopoietic stem and progenitor cells (HSPCs) to sustain tumor-associated myeloid production. Researchers assessed bone marrow from treatment-naïve patients with stage III breast cancer and used mouse models, transplantation assays, and single-cell RNA sequencing. The supplied abstract does not report patient numbers or quantitative effect estimates.

Both patients and mice exhibited expanded bone marrow HSPCs with enhanced myeloid output. In transplantation experiments, tumor-educated HSPCs retained a myeloid bias in healthy recipients and promoted tumor progression after a subsequent tumor challenge. Transplantation of long-term hematopoietic stem cells did not reproduce these effects, implicating downstream progenitors. Multipotent progenitor-3 cells (MPP3s) emerged as the principal drivers, while depletion of mature myeloid cells triggered rapid progenitor expansion and myeloid rebound in tumor-bearing mice.

Patient single-cell analyses showed reduced Wnt–β-catenin signaling in HSPCs. The researchers identified bone-derived DKK1, a Wnt inhibitor elevated during breast cancer progression, as a mediator of MPP3 reprogramming. Targeting DKK1 reduced tumor progression, MPP3 expansion, and myeloid output in mice, but also limited HSPC engraftment after transplantation. These findings suggest a potential upstream therapeutic target, not an established treatment strategy. Human efficacy and safety remain untested in the reported experiments, and assessment is limited to the abstract.