Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106,China.
Int J Mol Sci. 2022 Nov 30;23(23):15020. doi: 10.3390/ijms232315020.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by intra-tumoral heterogeneity, and patients are always diagnosed after metastasis. Thus, finding out how to effectively estimate metastatic risk underlying PDAC is necessary. In this study, we proposed scMetR to evaluate the metastatic risk of tumor cells based on single-cell RNA sequencing (scRNA-seq) data. First, we identified diverse cell types, including tumor cells and other cell types. Next, we grouped tumor cells into three sub-populations according to scMetR score, including metastasis-featuring tumor cells (MFTC), transitional metastatic tumor cells (TransMTC), and conventional tumor cells (ConvTC). We identified metastatic signature genes (MSGs) through comparing MFTC and ConvTC. Functional enrichment analysis showed that up-regulated MSGs were enriched in multiple metastasis-associated pathways. We also found that patients with high expression of up-regulated MSGs had worse prognosis. Spatial mapping of MFTC showed that they are preferentially located in the cancer and duct epithelium region, which was enriched with the ductal cells' associated inflammation. Further, we inferred cell-cell interactions, and observed that interactions of the ADGRE5 signaling pathway, which is associated with metastasis, were increased in MFTC compared to other tumor sub-populations. Finally, we predicted 12 candidate drugs that had the potential to reverse expression of MSGs. Taken together, we have proposed scMetR to estimate metastatic risk in PDAC patients at single-cell resolution which might facilitate the dissection of tumor heterogeneity.
胰腺导管腺癌（PDAC）的特点是肿瘤内异质性，并且患者总是在转移后被诊断出来。因此，找出如何有效地评估 PDAC 潜在的转移风险是必要的。在这项研究中，我们提出了 scMetR，以便根据单细胞 RNA 测序（scRNA-seq）数据评估肿瘤细胞的转移风险。首先，我们确定了多种细胞类型，包括肿瘤细胞和其他细胞类型。接下来，我们根据 scMetR 评分将肿瘤细胞分为三个亚群，包括具有转移特征的肿瘤细胞（MFTC）、过渡性转移肿瘤细胞（TransMTC）和常规肿瘤细胞（ConvTC）。我们通过比较 MFTC 和 ConvTC 来识别转移特征基因（MSGs）。功能富集分析表明，上调的 MSGs 富集在多个与转移相关的途径中。我们还发现，高表达上调 MSGs 的患者预后较差。MFTC 的空间映射显示，它们优先位于癌症和导管上皮区域，该区域富含与导管细胞相关的炎症。此外，我们推断了细胞-细胞相互作用，并观察到与转移相关的 ADGRE5 信号通路的相互作用在 MFTC 中比在其他肿瘤亚群中增加。最后，我们预测了 12 种可能具有逆转 MSGs 表达潜力的候选药物。总之，我们提出了 scMetR 来评估 PDAC 患者在单细胞分辨率下的转移风险，这可能有助于剖析肿瘤异质性。
