Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Int J Cancer. 2023 Dec 15;153(12):2055-2067. doi: 10.1002/ijc.34708. Epub 2023 Sep 1.
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.
前列腺癌（PCa）在分子组成和临床预后方面具有高度异质性。前列腺肿瘤微环境（TME）被认为在驱动疾病侵袭性方面发挥着重要作用，但确切的机制仍难以捉摸。在我们的研究中，我们首次使用空间转录组学来探索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，包括去势抵抗性（CRPC）和神经内分泌（NEPC）疾病阶段。在 CRPC 中，我们鉴定了一个 T 细胞簇，其活性可能被附近的调节性 T 细胞损害，可能介导侵袭性疾病表型。此外，我们在一个癌相关成纤维细胞（CAF）簇中鉴定了上皮-间充质转化的标志性特征，表明原发 TME 的侵袭性特征导致转移扩散。在 NEPC 中，我们鉴定了活跃的免疫-基质交叉对话，CAFs 和 M2 巨噬细胞之间存在显著的配体-受体相互作用。此外，我们鉴定了一个恶性细胞群体，与免疫相关基因特征的下调有关。在晚期 PCa 患者（SU2C 队列，n=99）中，该特征的低表达与基因组不稳定性水平升高相关，在早期 PCa 患者（TCGA 队列，n=395）中与无复发生存率差相关，提示其具有预后生物标志物的潜力。总之，我们的研究揭示了在空间分辨率上进行全转录组谱分析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。
