Background: Primary hepatocellular carcinoma (HCC) and liver metastases differ in origin, progression, and therapeutic response, yet a direct high-resolution spatial comparison of their tumor microenvironments (TMEs) within the liver has not previously been performed.Methods: We applied high-definition spatial transcriptomics to fresh-frozen specimens of one HCC and one liver metastasis (>16,000 genes per sample, >97% mapping rates) as a proof-of-principle two-specimen study, cross-validated in human proteomics and patients’ survival datasets. Transcriptional clustering revealed spatially distinct compartments, rare cell states, and pathway alterations, which were further compared against an independent systemic dataset.Results: HCC displayed an ordered lineage architecture, with transformed hepatocyte-like tumor cells broadly dispersed across the tissue and more differentiated hepatocyte-derived cells restricted to localized zones. By contrast, liver metastases showed two sharply compartmentalized domains: an invasion zone, where proliferative stem-like tumor cells occupied TAM-rich boundaries adjacent to hypoxia-adapted tumor-core cells, and a plasticity zone, which formed a heterogeneous niche of cancer–testis antigen–positive germline-like cells. Across both tumor types, we detected a conserved metabolic program of “porphyrin overdrive,” defined by reduced cytochrome P450 expression, enhanced oxidative phosphorylation gene expression, and upregulation ofFLVCR1andALOX5, reflecting coordinated rewiring of heme and lipid metabolism.Conclusions: In this pilot study, HCC and liver metastases demonstrated fundamentally different spatial architectures, with metastases uniquely harboring a germline/neural-like plasticity hub. Despite these organizational contrasts, both tumor types converged on a shared program of metabolic rewiring, highlighting potential therapeutic targets that link local tumor niches to systemic host–tumor interactions.
背景：原发性肝细胞癌（HCC）与肝转移癌在起源、进展及治疗反应上存在差异，但两者在肝脏内肿瘤微环境（TME）的高分辨率空间对比研究尚未见报道。方法：本研究采用高清空间转录组技术，对一例HCC和一例肝转移癌的新鲜冷冻标本（每个样本检测>16,000个基因，图谱匹配率>97%）进行原理验证性双标本研究，并通过人类蛋白质组学数据和患者生存数据集进行交叉验证。通过转录聚类分析揭示空间分隔的细胞区室、罕见细胞状态及通路改变，并与独立系统性数据集进行对比。结果：HCC呈现有序的谱系结构，转化型肝细胞样肿瘤细胞广泛分布于组织中，而分化程度更高的肝源性细胞局限于局部区域。相比之下，肝转移癌显示出两个明显分隔的域：侵袭区（增殖性干细胞样肿瘤细胞占据富含肿瘤相关巨噬细胞的边界区域，毗邻适应缺氧的肿瘤核心细胞）和可塑性区（形成癌症-睾丸抗原阳性生殖细胞样细胞的异质性生态位）。在两种肿瘤类型中，我们检测到保守的"卟啉代谢亢进"程序，其特征为细胞色素P450表达降低、氧化磷酸化相关基因表达增强以及FLVCR1和ALOX5上调，反映了血红素与脂质代谢的协同重编程。结论：本初步研究表明，HCC与肝转移癌具有根本不同的空间结构，其中转移癌独特地存在生殖细胞/神经样可塑性枢纽。尽管组织结构存在差异，但两种肿瘤类型均汇聚于共同的代谢重编程程序，这为连接局部肿瘤生态位与系统性宿主-肿瘤相互作用的潜在治疗靶点提供了新见解。
肿瘤(癌症)患者之家