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Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumor-propagating cells and their dynamic cellular transition during liver cancer progression

ABSTRACT: Hepatocellular carcinoma (HCC) is highly heterogeneous, and this heterogeneity contributes to therapeutic resistance and tumor recurrence. The aim of this study was to investigate the role, heterogeneity, and properties of Prom1+ cells in HCC in intact mouse models. We used Prom1C-L/+;Rosa26tdTomato/+ mice to establish two HCC mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing at different time points post-HCC induction. We ablated the Prom1+ cell population in Prom1C-L/+;Rosa26DTA/+ mice. Single cell RNA-seq (scRNA-seq) was carried out to analyse the lineage properties, heterogeneity, and dynamics of the traced Prom1+ cells in the chronic fibrotic HCC model. Bulk RNAseq was carried out to analyse the change in transcriptome in Prom1 depleted tumor.

ORGANISM(S): Mus musculus

PROVIDER: GSE181515 | GEO | 2021/10/04

REPOSITORIES: GEO

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Project description:Hepatocellular carcinoma (HCC) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC, we used a human disease-relevant mouse model of fibrosis-associated hepatocarcinogenesis. In this model, marked liver tumor response caused by a pro-mutagenic chemical N-nitrosodiethylamine in presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations (CNAs), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis-associated hepatocarcinogenesis. We evaluated DNA CNAs and changes in gene expression in the mouse liver (normal, tumor and non-tumor cirrhotic tissues). In addition, we compared our findings to those in human HCC (tumor and non-tumor cirrhotic/fibrotic tissues). We observed that while fibrotic liver tissue is largely devoid of DNA CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. When compared to CNAs in human HCC, we found that 33% of genes in these segments are similarly affected in the mouse tumors. Our results suggest that CNAs most commonly arise in neoplastic tissue rather than in fibrotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC. Genomic DNA was extracted from frozen liver samples from vehicle-control and DEN+CCl4-treated mice using a DNEasy kit (Qiagen, Valencia, CA). Eighteen mouse tumor samples were included in the study, as well as 18 matched non-tumor samples taken from fibrotic, non-tumorous, surrounding liver tissue from the same mice. Liver DNA from 6 vehicle control-mice was pooled and used as the reference genome in the aCGH experiments. Copy number alterations were identified using the normalized data.

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Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumor-propagating cells and their dynamic cellular transition during liver cancer progression

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