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Unique macrophage phenotypes activated by BMP signaling in breast cancer bone metastases
Claire L. Ihle, … , Elizabeth E. Smith, Philip Owens
Claire L. Ihle, … , Elizabeth E. Smith, Philip Owens
Published January 9, 2024
Citation Information: JCI Insight. 2024;9(1):e168517. https://doi.org/10.1172/jci.insight.168517.
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Research Article Immunology Oncology

Unique macrophage phenotypes activated by BMP signaling in breast cancer bone metastases

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Abstract

Metastatic breast cancer (mBC) tissue in bone was systematically profiled to define the composition of the tumor microenvironment. Gene expression identified a high myeloid signature of patients with improved survival outcomes. Bone metastases were profiled by spatial proteomics to examine myeloid populations within the stroma that correlated with macrophage functions. Single-cell spatial analysis uncovered macrophage activation in the stroma of mBC bone lesions. Matched BC patient samples of primary breast tumor and bone metastasis tissues were compared for gene expression in the bone, where bone morphogenetic protein 2 (BMP2) was most significantly upregulated. Immune cell changes from breast to bone demonstrated a loss of lymphoid cells but a consistent population of macrophages. BMP-activated macrophages were increased uniquely in bone. Bone marrow–derived macrophage activation coupled with BMP inhibition increased inflammatory responses. Using experimental mouse models of mBC bone metastasis and trained immunity, we found that BMP inhibition restricts progression of metastases early in the macrophage activation state but not after tumors were established in the bone. This study revealed unique myeloid BMP activation states that are distinctly integrated with bone metastases.

Authors

Claire L. Ihle, Desiree M. Straign, Johana A. Canari, Kathleen C. Torkko, Kathryn L. Zolman, Elizabeth E. Smith, Philip Owens

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Figure 5

BMP inhibition modulates a model of metastatic breast cancer in bone.

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BMP inhibition modulates a model of metastatic breast cancer in bone.
(A...
(A) Experimental scheme of BMDM isolation and treatment from mice stimulated with β-glucan. BMDM were treated with BMP inhibitor; after 24 hours, cells were stimulated with LPS for 24 hours. (B) BMDM Id1 gene expression. (C) BMDM Il-6 gene expression. (D) BMDM Tnf gene expression. (E) Experimental scheme for mouse model of bone metastasis with β-glucan stimulus and BMP inhibition (n = 5). Seven days prior to seeding a syngeneic bone metastasis cell line in the tibia, mice were stimulated with β-glucan. Twenty-eight–day osmotic pumps were implanted into mice 7 days after intratibial injection. (F) Intratibial tumor volume. (G) Peripheral blood PyMT gene expression. (H) Lung macrometastases. (I) Experimental scheme for mouse model of bone metastasis with β-glucan stimulus and BMP inhibition (n = 5). Seven days prior to seeding a bone metastasis cell line in the tibia, mice were stimulated with β-glucan, and 7-day osmotic pumps were implanted into mice. Intratibial injection of a syngeneic bone metastasis cell line was performed after 7 days. (J) Intratibial tumor volume. (K) Peripheral blood PyMT gene expression. (L) Lung macrometastases. (M) Experimental scheme for mouse model of bone metastasis with β-glucan stimulus in LysMCre CTL (n = 7) and LysMCre BMPR1a-cKO (n = 4) mice. Seven days prior to seeding a bone metastasis cell line in the tibia, mice were stimulated with β-glucan. (N) Kaplan-Meier curve of overall survival from intratibial bone metastasis seeding to mouse sacrifice or death. (O) Lung macrometastases. Data are presented as mean ± SEM. Statistical values determined by ordinary 1-way ANOVA followed by post hoc analysis for Tukey multiple comparisons (B–D). Statistical values determined by Student’s t test (F–H, J–L, and O). Statistical value determined by log-rank test (N).

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