Stereo-seq 空间转录组学揭示细胞类型对前列腺癌转移的贡献

Prostate cancer remains a significant cause of morbidity and mortality among men, with African-American (AA) men experiencing a disproportionate disease burden. Although molecular profiling has advanced our understanding, the cellular origins and spatial microenvironmental transitions that drive malignant progression and metastatic potential remain incompletely defined. To characterize these transitions, we performed high-resolution spatial transcriptomic profiling on benign (n = 1) and malignant (n = 2) prostate tissues obtained from three AA men using STEREO-seq (SpaTial Enhanced REsolution Omics-sequencing), generating 83,144 cell-bins across all samples. Data were processed using the STEREO-seq Analysis Workflow (SAW v6.0) and analyzed with Stereopy and Seurat. Cell-type annotation was performed using Azimuth with the Prostate Cell Atlas as a reference, and stringent quality filters (>20% mitochondrial RNA or annotation confidence <0.5) resulted in 63,861 high-confidence annotations. Spatial niche characterization was performed using QUICHE (QUantitative InterCellular nicHe Enrichment) to define microenvironmental structure and cell-cell ecosystems. Compositional analysis revealed a pronounced expansion of club epithelial (CE) cells in malignant tissues, with enrichment correlating with tumor grade, accompanied by a marked reduction in fibroblasts. CE cells in high-grade lesions showed strong upregulation of LTF (avg_log2FC = 6.92, padj = 7.9 × 10⁻⁶⁷), while fibroblasts exhibited widespread loss of actin-associated genes (ACTG2, ACTA2, ACTB), indicating cytoskeletal disruption and microenvironmental remodeling. Basal epithelial cells displayed near-complete loss of KRT15 expression (avg_log2FC = -4.92, padj = 6.1 × 10⁻²⁸¹), suggesting depletion of structural epithelial populations and glandular destabilization. QUICHE analysis revealed distinct tumor-associated spatial niches highly enriched for CE cells, whereas fibroblast-rich niches dominated benign regions. Differential niche-level expression recapitulated global transcriptomic patterns, including loss of tumor suppressor gene activity, architectural breakdown of glandular structures, and activation of pathways implicated in invasion and metastasis. These findings highlight substantial shifts in cellular composition and spatial organization accompanying malignant transformation in prostate cancer. ST profiling identified CE-cell-driven niches and transcriptomic signatures strongly associated with metastatic potential, offering novel biomarkers and spatially defined cellular interactions that improve our understanding of PCa progression in African-American men. This spatially resolved framework provides a foundation for future studies aimed at dissecting microenvironmental drivers of metastasis and developing cell-type-specific therapeutic strategies.