Abstract

Breast cancer progression is associated with systemic immune dysregulation characterized by the expansion of immunosuppressive myeloid populations that promote tumor progression, metastasis, and resistance to therapy. However, the mechanisms that sustain pathological myeloid expansion remain incompletely understood. In particular, it remains unknown whether solid tumors functionally reprogram hematopoietic stem and progenitor cells (HSPCs) to drive enhanced myeloid output and if bone-derived signals can regulate tumor-associated hematopoietic remodeling. In murine models of primary and metastatic breast cancer, tumor progression induced the remodeling of the hematopoietic compartment, characterized by the expansion of HSPCs, enhanced myeloid differentiation, and systemic accumulation of myeloid populations. Analysis of bone marrow from treatment-naïve breast cancer patients revealed a similar expansion of hematopoietic stem cells and multipotent progenitor populations with enhanced myeloid potential, supporting the clinical relevance of tumor-associated hematopoietic remodeling. Functional transplantation assays demonstrated that tumor-educated HSPCs displayed a competitive repopulation advantage and promoted tumor progression upon secondary challenge. In contrast, long-term hematopoietic stem cells (HSCs) alone did not sustain pathological myelopoiesis, indicating that downstream progenitor populations are major mediators of tumor-induced hematopoietic remodeling. Among progenitor subsets, multipotent progenitor 3 (MPP3) cells emerged as central drivers of tumor-associated myeloid expansion, displaying enhanced granulocyte-macrophage differentiation potential and activation of inflammatory-associated transcriptional programs. Mechanistically, we identified the bone-derived Wnt inhibitor Dickkopf-1 (Dkk1) as a regulator of tumor-associated hematopoietic reprogramming. We previously demonstrated that Dkk1 expression increases during breast cancer progression. Here, we found that Dkk1 enhanced the myeloid differentiation potential of MPP3 cells, whereas genetic deletion or therapeutic neutralization of Dkk1 reduced MPP3 expansion, restored hematopoietic balance, and suppressed tumor progression. These findings establish a tumor-bone-HSPC signaling axis in which primary tumors reprogram bone marrow resident HSPCs to sustain pathological myeloid output and systemic immune suppression. Breast cancer bone metastases remain a major clinical challenge due to the complex interactions between tumor cells, immune populations, and the bone microenvironment that support metastatic growth. Although therapies targeting osteoclast-mediated bone remodeling reduce skeletal-related complications and delay disease progression, they do not eliminate established metastatic lesions. Given the established roles of both myeloid populations and osteoclast-mediated bone remodeling in supporting tumor progression, we evaluated the therapeutic efficacy of targeting these compartments in murine models of skeletal metastasis. While anti-Gr1-mediated depletion of myeloid cells effectively reduced primary tumor growth, it failed to reduce skeletal tumor burden and instead expanded a bone marrow-resident CD11b⁺Ly6CintLy6Gint population with osteoclastogenic potential, resulting in increased numbers of TRAP-positive cells within skeletal tumors. In contrast, combined targeting of Gr1⁺ myeloid cells and osteoclast-mediated bone remodeling using Zoledronic Acid significantly reduced established skeletal metastases compared with either treatment alone. These findings demonstrate that myeloid populations and osteoclast-mediated bone remodeling play complementary roles in sustaining skeletal metastases and indicate that effective treatment of bone metastatic disease requires coordinated targeting of both immune and skeletal compartments. Collectively, this work demonstrates that breast cancer induces durable hematopoietic reprogramming that extends beyond expansion of mature immune populations to upstream hematopoietic progenitors. These studies identify MPP3 cells and bone-derived Dkk1 as key regulators of tumor-associated myeloid bias and establish a tumor-bone-HSPC signaling axis that promotes pathological myelopoiesis during disease progression. Furthermore, studies in skeletal metastasis reveal that therapeutic targeting of myeloid populations alone is insufficient to suppress tumor growth within bone because of compensatory osteoclastogenic responses within the bone microenvironment. Instead, concurrent inhibition of myeloid populations and osteoclast-mediated bone remodeling is required for optimal control of skeletal disease. Together, these findings identify hematopoietic remodeling as a therapeutic vulnerability in breast cancer and highlight the importance of coordinated targeting of both immune and bone compartments to improve outcomes in advanced disease.

Committee Chair

Roberta Faccio

Committee Members

Daniel Link; Grant Challen; Katherine Weilbaecher; Kyunghee Choi

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-6-2026

Language

English (en)

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Oncology Commons

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