生物
癌症研究
干细胞
转录组
移植
癌症
基因签名
癌细胞
肿瘤异质性
肝细胞癌
病理
细胞生物学
癌症干细胞
基因
医学
遗传学
内科学
基因表达
作者
Lei Zhou,Ken HO Yu,Tin Lok Wong,Zhao Zhang,Chun Ho Chan,Jane Hc Loong,Noélia Che,Hua Yu,Kel Vin Tan,Man Tong,Esw Ngan,Joshua W. K. Ho,Stephanie Ma
出处
期刊:Gut
[BMJ]
日期:2021-09-29
卷期号:: gutjnl-324321
被引量:34
标识
DOI:10.1136/gutjnl-2021-324321
摘要
Hepatocellular carcinoma (HCC) has high intratumoral heterogeneity, which contributes to therapeutic resistance and tumour recurrence. We previously identified Prominin-1 (PROM1)/CD133 as an important liver cancer stem cell (CSC) marker in human HCC. The aim of this study was to investigate the heterogeneity and properties of Prom1+ cells in HCC in intact mouse models.We established two mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing post-HCC induction using Prom1C-L/+; Rosa26tdTomato/+ mice, and targeted depletion using Prom1C-L/+; Rosa26DTA/+ mice. Single-cell RNA sequencing (scRNA-seq) was carried out to analyse the transcriptomic profile of traced Prom1+ cells.Prom1 in HCC tumours marks proliferative tumour-propagating cells with CSC-like properties. Lineage tracing demonstrated that these cells display clonal expansion in situ in primary tumours. Labelled Prom1+ cells exhibit increasing tumourigenicity in 3D culture and allotransplantation, as well as potential to form cancers of differential lineages on transplantation. Depletion of Prom1+ cells impedes tumour growth and reduces malignant cancer hallmarks in both HCC models. scRNA-seq analysis highlighted the heterogeneity of Prom1+ HCC cells, which follow a trajectory to the dedifferentiated status with high proliferation and stem cells traits. Conserved gene signature of Prom1 linage predicts poor prognosis in human HCC. The activated oxidant detoxification underlies the protective mechanism of dedifferentiated transition and lineage propagation.Our study combines in vivo lineage tracing and scRNA-seq to reveal the heterogeneity and dynamics of Prom1+ HCC cells, providing insights into the mechanistic role of malignant CSC-like cells in HCC progression.
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