前列腺癌（PCa）在分子构成和临床预后方面表现出高度的异质性。前列腺肿瘤微环境（TME）被假设在促进疾病恶性程度方面起着重要作用，但精确机制仍然不明确。本研究中，我们首次使用空间转录组学方法探索了来自转移性疾病患者原发前列腺肿瘤内的空间基因表达异质性。总共，我们分析了来自3名PCa患者的5459个组织点，包括阉割抵抗性（CRPC）和神经内分泌（NEPC）疾病阶段。在CRPC中，我们发现了一个T细胞簇，其活性可能受到附近调节性T细胞的损害，潜在地介导了恶性疾病表型。此外，在与癌相关的间质细胞簇中，我们发现了上皮间质转化的标志性特征，表明了原发TME的恶性特征导致转移性扩散。在NEPC中，我们发现了免疫-间质相互作用的活跃性，例如间质细胞与M2巨噬细胞之间的显著配体受体相互作用。此外，我们发现与免疫相关基因签名下调有关的恶性细胞群体。在晚期PCa患者（SU2C队列，n = 99）中，较低的表达与更高水平的基因组不稳定性以及早期阶段PCa患者（TCGA队列，n = 395）中较差的无复发生存率相关，表明了预后生物标志物的潜力。综上，我们的研究揭示了在空间分辨率下进行全转录组追踪对于生物标志物发现和推进我们对肿瘤生物学的理解的重要性。© 2023 The Authors. International Journal of Cancer 由 John Wiley & Sons Ltd 代表 UICC 出版。

Prostate cancer (PCa) is a highly heterogeneous disease in terms of its molecular makeup and clinical prognosis. The prostate tumor microenvironment (TME) is hypothesized to play an important role in driving disease aggressiveness, but precise mechanisms remain elusive. In our study, we used spatial transcriptomics to explore for the first time the spatial gene expression heterogeneity within primary prostate tumors from patients with metastatic disease. In total, we analyzed 5459 tissue spots from three PCa patients comprising castration-resistant (CRPC) and neuroendocrine (NEPC) disease stages. Within CRPC, we identified a T cell cluster whose activity might be impaired by nearby regulatory T cells, potentially mediating the aggressive disease phenotype. Moreover, we identified Hallmark signatures of epithelial-mesenchymal transition in a cancer-associated fibroblast (CAF) cluster, indicating the aggressive characteristic of the primary TME leading to metastatic dissemination. Within NEPC, we identified active immune-stroma cross-talk exemplified by significant ligand-receptor interactions between CAFs and M2 macrophages. Further, we identified a malignant cell population that was associated with the down-regulation of an immune-related gene signature. Lower expression of this signature was associated with higher levels of genomic instability in advanced PCa patients (SU2C cohort, n = 99) and poor recurrence free survival in early-stage PCa patients (TCGA cohort, n = 395), suggesting prognostic biomarker potential. Taken together, our study reveals the importance of whole transcriptome profiling at spatial resolution for biomarker discovery and for advancing our understanding of tumor biology.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.