Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma
Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma
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单细胞 RNA-seq 强调胰腺导管腺癌的瘤内异质性和恶性进展
DOI：
10.1038/s41422-019-0195-y
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发表时间：
2019-09-01
期刊：
影响因子：
44.1
通讯作者：
Wu, Wenming
中科院分区：
文献类型：
--
作者：
Peng, Junya;Sun, Bao-Fa;Wu, Wenming
胰腺导管腺癌（PDAC）是最常见的胰腺癌类型，具有高度的肿瘤内异质性和不良预后。为了全面描述PDAC肿瘤内异质性和PDAC进展的潜在机制，我们采用单细胞RNA-seq（scRNA-seq）获得了来自原发性PDAC肿瘤和对照胰腺的57，530个个体胰腺细胞的转录组图谱，并鉴定了不同的恶性和基质细胞类型，包括PDAC中分别具有异常和恶性基因表达谱的两种导管亚型。我们发现，异质性恶性亚型是由几个亚群的差异增殖和迁移的潜力。细胞轨迹分析显示，多种肿瘤相关通路和转录因子（TF）的组分在沿着PDAC进展中差异表达。此外，我们发现具有独特增殖特征的导管细胞亚群与肿瘤浸润T细胞的失活状态相关，为预测抗肿瘤免疫反应提供了新的标志物。总之，我们的研究结果为破译PDAC中的肿瘤内异质性提供了宝贵的资源，并揭示了肿瘤内在转录状态与T细胞活化之间的联系，为抗癌治疗（如靶向治疗和免疫治疗）提供了潜在的生物标志物。
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. To comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, we employed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases, and identified diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, in PDAC. We found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, we found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, our findings provide a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.