Unique macrophage phenotypes activated by BMP signaling in breast cancer bone metastases
Claire L. Ihle, Desiree M. Straign, Johana A. Canari, Kathleen C. Torkko, Kathryn L. Zolman, Elizabeth E. Smith, Philip Owens
Claire L. Ihle, Desiree M. Straign, Johana A. Canari, Kathleen C. Torkko, Kathryn L. Zolman, Elizabeth E. Smith, Philip Owens
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Research Article Immunology Oncology

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

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 3

Comparative analysis of human breast cancer primary tumor and bone metastasis immune microenvironment.

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Comparative analysis of human breast cancer primary tumor and bone metas...
(A) Volcano plot of differential gene expression analysis from nCounter IO 360 gene expression analysis of mBC bone metastases compared with the baseline of matched primary tumors (n = 11). Genes upregulated in bone metastases are shown on the right (red region), and genes upregulated in primary tumors are shown on the left (blue region). (B) Undirected gene set enrichment pathway analysis of bone metastases versus primary tumor gene expression. Global significance scores greater than 1 revealed pathways significantly upregulated in bone metastases compartment–matched primary BC tumors. (C) Cell type gene signature scores for primary tumors and bone lesions. (D) Polaris mIHC representative image of spectrally unmixed mBC patient primary tumor and matched bone metastasis (n = 16). Dotted white line indicates tumor-stroma boundary. (E) Cellular phenotype counts in primary tumor and bone metastasis whole FOV images. (F) Cellular phenotype counts in the tumor tissue segments of primary tumor and bone metastasis samples. (G) Cellular phenotype counts in the stromal tissue segments of primary tumor and bone metastasis samples. Data are presented as mean ± SEM. Statistical values determined by Student’s t test (C and E–G).