Yu Yan-Ping, Obert Caroline, Ren Bao-Guo, Krivit Marielle, Metcalfe Kyle, Liu Jia-Jun, Ben-Yehezkel Tuval, Liu Silvia, Luo Jian-Hua
Departments of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Element Biosciences Inc., San Diego, CA, United States.
Front Cell Dev Biol. 2025 Jun 3;13:1600129. doi: 10.3389/fcell.2025.1600129. eCollection 2025.
Hepatocellular carcinoma (HCC) is one of the most lethal cancers for humans. HCC is highly heterogeneous. In this study, we performed ultra-depth (∼1 million reads per spot) sequencing of 6,320 spatial transcriptomes on a case of HCC. Sixteen distinct spatial expression clusters were identified. Each of these clusters was spatially contiguous and had distinct gene expression patterns. In contrast, benign liver tissues showed minimal heterogeneity in terms of gene expression. Numerous immune cell-enriched spots were identified in both HCC and benign liver regions. Cells adjacent to these immune cell-enriched spots showed significant alterations in their gene expression patterns. Interestingly, the responses of HCC cells to the nearby immune cells were significantly more intense and broader, while the responses of benign liver cells to immune cells were somewhat narrow and muted, suggesting an innate difference in immune cell activities towards HCC cells in comparison with benign liver cells. However, cell-cell interaction analyses showed significant immune evasion by HCC cancer cells. When standard-depth sequencing was performed, significant numbers of genes and pathways that were associated with these changes disappeared. Qualitative differences in some pathways were also found. These results suggest that deep spatial sequencing may help to uncover previously unidentified mechanisms of liver cancer development.
肝细胞癌（HCC）是对人类最致命的癌症之一。HCC具有高度异质性。在本研究中，我们对一例HCC的6320个空间转录组进行了超深度测序（每个位点约100万条 reads）。鉴定出16个不同的空间表达簇。这些簇中的每一个在空间上都是连续的，并且具有不同的基因表达模式。相比之下，良性肝组织在基因表达方面显示出最小的异质性。在HCC和良性肝区域均鉴定出大量富含免疫细胞的位点。与这些富含免疫细胞的位点相邻的细胞在其基因表达模式上显示出显著变化。有趣的是，HCC细胞对附近免疫细胞的反应明显更强烈、更广泛，而良性肝细胞对免疫细胞的反应则有些狭窄且微弱，这表明与良性肝细胞相比，免疫细胞对HCC细胞的活性存在固有差异。然而，细胞间相互作用分析显示HCC癌细胞存在显著的免疫逃逸。当进行标准深度测序时，与这些变化相关的大量基因和通路消失了。还发现了一些通路的定性差异。这些结果表明，深度空间测序可能有助于揭示先前未被发现的肝癌发生机制。
