前列腺癌种植前后骨髓微环境的高分辨率空间转录组图谱

Prostate cancer is the second leading cause of cancer-related death in men, and nearly 80% of patients develop skeletal metastases. However, how primary prostate tumors sculpt the bone microenvironment prior to or during the earliest stages of metastatic spread remains poorly understood. To fill this gap, we generated a spatiotemporal map of tumor-induced changes in the bone marrow using an immunocompetent syngeneic mouse model of prostate cancer (RM1; C57BL/6).Using whole-genome Visium HD spatial transcriptomics, we profiled bone microenvironments from (1) tumor-naïve mice, (2) mice bearing primary prostate tumors but lacking bone metastases (pre-metastatic), and (3) early metastatic mice following intra-arterial delivery of RM1 cells. We interrogated these datasets using a comprehensive bioinformatic workflow (Seurat, GPTcelltype, Banksy, STenrich, Monocle, and CellChat) to resolve coordinated stromal and immune remodeling as disease progresses. We discovered that primary prostate tumors initiate mixed bone-remodeling programs characterized by sustained osteoclast activation and a progressive collapse of osteoblast differentiation. Consistent with this, microCT imaging revealed measurable bone loss in pre-metastatic mice, which intensified upon metastatic colonization. Within the immune compartment, we found a concomitant disruption of plasma cells, possibly driven by the loss of osteoblasts which are key niche cells required for normal plasma cell recruitment and survival. Unexpectedly, despite inoculation with a genetically homogeneous RM1 line, we observed that early metastatic lesions diverged into two transcriptionally distinct tumor populations occupying separate spatial neighborhoods. The proximal, trabecular-associated lesion is embedded in a stromal-rich niche and shows upregulation of hypoxia- and oxidative stress-related programs. In contrast, the distal lesion in a more immune-dense region exhibits heightened interferon signaling. These findings demonstrate that local bone microenvironments impose divergent selective pressures on metastatic tumors , shaping their phenotypic evolution. Together, our work provides a high-resolution spatiotemporal atlas of prostate cancer progression to bone, illuminating early stromal and immune perturbations that may prime the bone for metastatic takeover. This dataset serves as a platform for hypothesis generation and identifies potentially targetable microenvironmental mechanisms for preventing or treating bone metastatic prostate cancer.