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Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Breast Cancer Bone Metastasis

ABSTRACT: The presence of disseminated tumor cells in patient bone marrow (BM) aspirates predicts decreased recurrence-free survival, yet little is known about whether hematopoietic BM cells impact bone metastases. Here, we report that the BM can be rendered metastasis-suppressive by the bone-targeting bisphosphonate, zoledronic acid (ZA). In particular, ZA modulates hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to render them metastasis-suppressive. Granulocyte-colony stimulating factor (G-CSF) promotes resistance to ZA by re-directing M/OCP differentiation. We identified BM transcriptional programs that associate with metastasis suppression and resistance to ZA. Analysis of patient blood samples taken at randomization revealed that women with plasma G-CSF levels >23 pg/mL experienced significantly worse outcome with adjuvant ZA than those on ZA who had lower plasma G-CSF levels. Our findings establish that hematopoietic cells and M/OCP lineage potential profoundly impact bone metastasis and support the discovery of biomarkers that stratify therapeutic responses in patients at risk of recurrence.

ORGANISM(S): Mus musculus

PROVIDER: GSE108250 | GEO | 2021/02/25

REPOSITORIES: GEO

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Sca1+ macrophages activate hematopoietic stem/progenitor cells upon bone marrow stress. [RNA-Seq]

Project description:Although hematopoietic stem and progenitor cells (HSPCs) become activated in the cell-cycle status after chemotherapy to supply hematopoietic loss, the detailed mechanisms of activation remain unknown. Here we show that Sca1+ macrophages play a key role for bone marrow (BM) recovery through granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. By analyzing gene expression profiles of HSPCs lodged in 5-fluolouracil (5-FU)-treated mice, we found GM-CSF as a key proliferative signal. Sca1+ macrophages in BM after 5-FU treatment expressed high levels of GM-CSF. GM-CSF-knockout mice treated with 5-FU were lethal because of severe BM suppression. Up-regulation of Csf2 in Sca1+ macrophages by 5-FU was suppressed in MyD88-knockout mice, suggesting that TLR signaling via damage-associated molecular patterns caused by cell death is critical for up-regulation of Csf2. In 5-FU treated BM, majority of Sca1+ macrophages and transplanted HSPCs locate perivascular areas. These findings together indicate that Sca1+ macrophages induce HSPCs to proliferate through GM-CSF signaling in the stressed BM environments.

2021-01-20 | GSE120111 | GEO

Sca1+ macrophages activate hematopoietic stem/progenitor cells upon bone marrow stress. [scRNA-Seq]

2021-01-20 | GSE120112 | GEO

Single-cell RNA sequencing characterizes the comparision between Granulocyte-colony stimulating factor (G-CSF) primed human bone marrow and unstimulated bone marrow

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2022-06-23 | GSE193138 | GEO

Comparison of gene expression profile between primary and bone metastasized cancers

Project description:Bone metastasis occurs frequently in cancer patients. Conventional therapies have limited therapeutic outcomes, and thus, exploring the mechanisms of cancer progression in the bone metastasis is important to develop new effective therapies. In the bone microenvironment, adipocytes are the major stromal cells that interact with cancer cells during the bone metastasis. However, the comprehensive functions of bone marrow adipocytes in cancer progression are not yet fully understood. To address this, we investigated the role of bone marrow adipocytes on cancer cells, by focusing on an invasive front which reflects the direct effects of stromal cells on caner. In comprehensive histopathological and genetic analysis using bone metastasis specimens, we examined invasive fronts in bone metastasis and compared invasive fronts with adipocyte-rich bone marrow (adipo-BM) to those with hematopoietic cell-rich bone marrow (hemato-BM) as a normal counterpart of adipocytes. We found morphological complexity of invasive front with adipo-BM was significantly higher than that with hemato-BM. Based on immunohistochemistry, the invasive front with adipo-BM comparatively had significantly increased cancer-associated fibroblasts (CAFs) marker-positive area and lower density of CD8 positive lymphocytes compared to that with hemato-BM. RNA-seq analysis of primary and bone metastasis cancer reveals that bone metastasized cancer cells acquired drug resistance related gene expression phenotypes. Clearly, these findings indicate that bone marrow adipocytes provide favorable tumor microenvironment for cancer invasion and therapeutic resistance of bone metastasized cancers via CAF induction and immune evasion, providing a potential target for the treatment of bone metastasis.

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2023-12-01 | GSE248234 | GEO

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Project description:Bone marrow cells (BM) were isolated and primed with M-CSF (M BMDM) or GM-CSF (GM BMDM) for 7 days. M-BMDMs were treated with IL6 (20 ng/ml) for 3 h or 24 h while GM-BMDMs were treated for 3 h. The difference between BM, M-BMDM, and GM-BMDM were analyzed to describe the phenotye and function of each population. Moreover, by RNA-seq analysis, the influence of IL6 treatment on GM-BMDMs and M-BMDMs were analyzed.

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Project description:CD11bloLy6CloLy6Glo cells were sorted from the steady-state bone marrow (BM) of B6 mice, i.e. cells cultured for 5 d without human BM-derived mesenchymal stromal cells (MSCs) in the absence of GM-CSF. CD11bhiLy6ChiLy6Glo cells were isolated from BM cells cultured for 5 d under GM-CSF incubation (40 ng/ml) but without MSC coculture. CD11bmidLy6CmidLy6Glo cells were sorted from GM-CSF-stimulated, MSC-cocultured BM cells.

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