Molecular Subgroups of Intrahepatic Cholangiocarcinoma Discovered by Single-Cell RNA Sequencing-Assisted Multiomics Analysis
Molecular Subgroups of Intrahepatic Cholangiocarcinoma Discovered by Single-Cell RNA Sequencing-Assisted Multiomics Analysis
复制标题
通过单细胞 RNA 测序辅助多组学分析发现肝内胆管癌的分子亚组。
DOI：
10.1158/2326-6066.cir-21-1101
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发表时间：
2022-07-01
影响因子：
10.1
通讯作者：
Ruan, Jian
中科院分区：
文献类型：
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作者：
Bao, Xuanwen;Li, Qiong;Ruan, Jian
肝内胆管癌（ICC）是一种相对罕见但高度侵袭性的肿瘤类型，对化疗和免疫治疗反应不佳。 ICC 的全面分子表征对于新型疗法的开发至关重要。在这里，我们构建了来自两个临床中心的两个独立队列。通过蛋白质组学、全外显子组测序 (WES) 和单细胞 RNA 测序 (scRNA-seq) 对 ICC 进行了全面的多组学分析。新的 ICC 肿瘤亚型是在训练队列 (n=110) 中使用蛋白质组特征及其相关激活途径衍生出来的，并在验证队列 (n=41) 中得到进一步验证。确定了 ICC 中具有不同预后的三种分子亚型：染色质重塑、代谢和慢性炎症。慢性炎症亚型与不良预后相关。我们的随机森林算法显示，赖氨酸甲基转移酶 2D (KMT2D) 的突变经常发生在代谢亚型中，并且与较低的炎症活动相关。 scRNA-seq 进一步鉴定出 APOE+C1QB+ 巨噬细胞亚型，该亚型显示出重塑慢性炎症亚型的能力，并导致 ICC 的不良预后。总之，通过单细胞转录组辅助的多组学分析，我们鉴定了 ICC 的新分子亚型，并验证了 APOE+C1QB+ 肿瘤相关巨噬细胞 (TAM) 作为针对 ICC 的潜在免疫治疗靶点。
Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly aggressive tumor type that responds poorly to chemotherapy and immunotherapy. Comprehensive molecular characterization of ICC is essential for the development of novel therapeutics. Here, we constructed two independent cohorts from two clinic centers. A comprehensive multi-omics analysis of ICC via proteomic, whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-seq) was performed. Novel ICC tumor subtypes were derived in the training cohort (n=110) using proteomic signatures and their associated activated pathways, which was further validated in a validation cohort (n=41). Three molecular subtypes, chromatin remodeling, metabolism, and chronic inflammation, with distinct prognoses in ICC were identified. The chronic inflammation subtype associated with a poor prognosis. Our random forest algorithm revealed that mutation of lysine methyltransferase 2D (KMT2D) frequently occurred in the metabolism subtype and associated with lower inflammatory activity. scRNA-seq further identified an APOE+C1QB+ macrophage subtype, which showed the capacity to reshape the chronic inflammation subtype and contribute to a poor prognosis in ICC. Altogether, with single-cell transcriptome-assisted multi-omics analysis, we identified novel molecular subtypes of ICC and validated APOE+C1QB+ tumor-associated macrophages (TAMs) as potential immunotherapy targets against ICC.