Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Breast Cancer Bone Metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA422921 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7165930.fastq.gz | Fastqsanger.gz | |||
| SRR7165940.fastq.gz | Fastqsanger.gz | |||
| SRR7165950.fastq.gz | Fastqsanger.gz | |||
| SRR7165960.fastq.gz | Fastqsanger.gz | |||
| SRR7165931.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:The presence of disseminated tumor cells in breast cancer patient bone marrow aspirates predicts decreased recurrence-free survival. Although it is appreciated that physiologic, pathologic, and therapeutic conditions impact hematopoiesis, it remains unclear whether targeting hematopoiesis presents opportunities for limiting bone metastasis. Using preclinical breast cancer models, we discovered that marrow from mice treated with the bisphosphonate zoledronic acid (ZA) are metastasis-suppressive. Specifically, ZA modulated hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to activate metastasis-suppressive activity. Granulocyte-colony stimulating factor (G-CSF) promoted ZA resistance by redirecting M/OCP differentiation. We identified M/OCP and bone marrow transcriptional programs associated with metastasis suppression and ZA resistance. Analysis of patient blood samples taken at randomization revealed that women with high-plasma G-CSF experienced significantly worse outcome with adjuvant ZA than those with lower G-CSF levels. Our findings support discovery of therapeutic strategies to direct M/OCP lineage potential and biomarkers that stratify responses in patients at risk of recurrence.Significance: Bone marrow myeloid/osteoclast progenitor cell lineage potential has a profound impact on breast cancer bone metastasis and can be modulated by G-CSF and bone-targeting agents. Cancer Res; 78(18); 5300-14. ©2018 AACR.
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Project description:Current lack of insight into mechanisms governing breast cancer metastasis has precluded development of curative therapies. Metastasis-initiating cells (MICs) are cancer cells uniquely equipped to establish metastatic outgrowths and are thought to cause recurrence and therapeutic resistance. Using various models of early metastatic disease, we have uncovered mechanisms by which certain primary tumors can prevent MICs from generating secondary tumors. In such cases, the primary tumor elicits a systemic immune response involving IL-1β expressing innate inflammatory cells that infiltrate the distant MIC microenvironment. Elevated IL-1β levels at the metastatic site prevent MICs from generating their highly proliferative E-cadherin-positive epithelial progeny. Thus, when the inherent plasticity of MICs is impeded, robustly growing tumors cannot be established. Ablation of the pro-inflammatory response or IL-1R inhibition relieves the block in differentiation and results in MIC colonization. Our data reveal complex and potentially life-prolonging interactions that occur between primary tumors and disseminated MICs that could be exploited to improve survival of patients at risk for metastatic disease.
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Project description:The bone marrow (BM) is the third most frequent site of metastasis for solid tumors, creating an unfavorable clinical outcome. It provides a unique microenvironment that promotes growth of tumors, however, the role of different BM cells, their molecular features, and their interactions with tumor cells, are poorly defined. Here, we investigate the BM niche in neuroblastoma (NB), a pediatric cancer of the sympathetic nervous system. NB has been molecularly defined at the primary cancer site, yet, the metastatic site is poorly characterized. We performed single-cell transcriptomics (scRNA-seq) and epigenomic profiling (scATAC-seq) of BM aspirates from 11 subjects spanning three major NB subtypes: patients with MYCN amplification (MNA), ATRX mutations (ATRXmut), and cases that lack these alterations (sporadic): NB cases were then compared to five age-matched and metastasis-free BM (controls), followed by in-depth single cell analyses of tissue diversity and cell-cell interactions. We present the first map of the epigenetic and transcriptomic effects of bone marrow metastases. Our analyses demonstrate that tumor cells in the metastatic niche display plasticity that differs among NB subtypes. NB cells via cell-cell interaction signal to the bone marrow microenvironment, rewiring specifically monocytes, which exhibit M1 and M2 features, marked by activation of pro- and anti-inflammatory programs, and express tumor-promoting factors, reminiscent of tumor-associated macrophages. Our study may provide the basis for a therapeutic approach, targeting tumor-to-microenvironment interactions.
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