ATF3 Reprograms the Bone Marrow Niche in Response to Early Breast Cancer Transformation

Area of Science:

• Oncology
• Stem Cell Biology
• Immunology

Background:

• Cancer is a systemic disease that can alter the bone marrow (BM) microenvironment.
• Tumor-derived signals can uniquely impact different BM subpopulations.
• Mesenchymal stem cells (MSCs) are implicated in mediating cancer's effects on the BM niche.

Purpose of the Study:

• To identify early cellular sensors and mediators of BM reprogramming in response to distal cancer.
• To elucidate the signaling pathways involved in cancer-induced alterations of the BM niche.
• To explore the potential of identified pathways and molecules as diagnostic markers and therapeutic targets.

Main Methods:

• Utilized a spontaneous mammary carcinoma model.
• Investigated the role of BM MSCs in sensing cancer cells and mediating BM reprogramming.
• Analyzed the IL1B/ATF3 signaling pathway in hematopoietic stem cells and myeloid differentiation.
• Assessed ATF3 expression in peripheral blood mononuclear cells for diagnostic potential.

Main Results:

• BM MSCs act as early sensors of distal cancer cells, initiating BM reprogramming.
• IL1B released by MSCs upregulates ATF3 in hematopoietic stem cells, promoting myeloid progenitor formation and differentiation.
• Deletion of ATF3 in myeloid cells reduces monocytes and impairs their differentiation into tumor-associated macrophages.
• ATF3 expression in peripheral blood CD14+ cells correlates with CD11b+ population expansion, distinguishing malignant from benign conditions.

Conclusions:

• The IL1B/ATF3 signaling pathway in the BM drives tumor-promoting emergency myelopoiesis.
• ATF3 shows potential as a circulating biomarker for early cancer detection.
• IL1B inhibition may offer a therapeutic strategy for breast cancer treatment.