The Role of Bone Marrow Erythroblastic Niche in Supporting metastatic Growth [BulkRNAseq]

Bone metastasis significantly compromises quality of life in advanced-stage breast cancer patients through severe pain, fractures, and decreased mobility. The role of bone-resident cells such as osteoblasts and osteoclasts in metastatic interactions is well-established, however, the contribution of hematopoietic stem cell (HSC) lineage cells in the bone marrow, which differentiate into both red and white blood cells, remains poorly understood. Employing an in vivo metastatic niche labeling system and single-cell RNA sequencing, we systematically identified and functionally validated novel stromal components critical for bone metastasis. This niche labeling system enabled metastatic cancer cells to directly label surrounding niche cells in vivo via mCherry secretion. Bone marrow cells proximal to the tumor, which absorbed the secreted mCherry, were characterized using single-cell RNA sequencing. Our analysis revealed a distinct macrophage population enriched in the metastatic niche. Further in-depth characterization of these niche-specific macrophages was performed through cell sorting and bulk RNA sequencing. This population was found to be specialized macrophages with iron metabolism capabilities, residing within the erythroid island to support erythropoiesis. We demonstrated that in the bone metastasis environment breast cancer cells hijacked the iron-rich macrophages to supply themselves with iron. To better survive in the hypoxic bone marrow microenvironment, tumor cells mimic erythroblasts by upregulating globin gene expression and heme synthesis genes. These findings underscore the critical role of iron-rich macrophages in supporting tumor growth in the bone and their significant impact on erythropoiesis, presenting novel therapeutic targets for managing bone metastasis and cancer-related anemia.