Single-Cell Transcriptomics of Liver Cancer: Hype or Insights?

Zhang, Qingyang; Ho, Daniel Chi Wing; Tsui, Y; Ng, Irene Oi–Lin

doi:10.1016/j.jcmgh.2022.04.014

Cited by 9 publications

(6 citation statements)

References 66 publications

(153 reference statements)

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“…Single-cell sequencing enables the study of complex cell populations, revealing interactions, developmental trajectories, and gene regulatory relationships (24,25). Although single-cell sequencing is extensively used in HCC research for immune cell lineages (lymphocytes and myeloid cells) (9), stromal cells (cancer-associated broblasts and tumor-associated endothelial cells) (10,11), and malignant cells (cancer stem cells (CSC), circulating tumor cells (CTC), induced pluripotent stem cells (iPSC))( 9), further exploration of malignant cell sub-populations is warranted. Investigating the key genes that drive the impact of malignant cells in HCC is crucial for comprehensive understanding.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, single-cell sequencing technology in HCC research mainly focuses on immune cell lineages (lymphocytes and myeloid cells) (9), stromal cells (cancer-associated broblasts and tumor-associated endothelial cells) (10,11), and malignant cells (cancer stem cells, circulating tumor cells, induced pluripotent stem cells, etc.) (9). However, there is limited analysis on malignant cell heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

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Unveiling the Dual Expression of Haptoglobin in Malignant Hepatocellular Carcinoma Cells through Single-Cell and Bulk RNA Sequencing Analysis

Du,

Liu,

Hao

et al. 2023

Preprint

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Hepatocellular carcinoma (HCC) is a highly prevalent and deadly cancer. Existing single-cell transcriptome research on HCC mainly focuses on immune and stromal cells, with limited analysis of malignant cell heterogeneity. In our study, we identified the key subgroup (subgroup 6) of HCC malignant cells with conflicting survival outcomes, and found haptoglobin (HP) as the key gene. Our analysis suggests that HP plays a tumor suppressive role in malignant cells, but has a negative correlation with immunity. Down-regulation of HP expression in HCC immune cells promotes Th1 cell-associated markers expression and reduces the differentiation of Th2 cells to Th1 cells, indirectly suppressing tumor growth. In malignant cells, up-regulation of HP expression to inhibit tumors is associated with the expression of malignant genes. At the same time, the up-regulation of HP expression in Pyridoxine inhibition of HCC is related to Metabolic pathways, Complement and coagulation cascades, Metabolism of xenobiotics by cytochrome P450, Retinol metabolism, Drug metabolism - cytochrome P450, Drug metabolism - other enzymes, Chemical carcinogenesis - DNA adducts, Bile secretion, and Biosynthesis of cofactors. Our study identified HP, a tumor suppressor gene in the malignant cell subpopulation of HCC, which exerts tumor suppressive effects through different mechanisms in immune cells and malignant cells, providing a new reference for the clinical treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unveiling the Dual Expression of Haptoglobin in Malignant Hepatocellular Carcinoma Cells through Single-Cell and Bulk RNA Sequencing Analysis

Du,

Liu,

Hao

et al. 2023

Preprint

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show abstract

“…On the other hand, prior studies [10] exploring HCC at the single-cell level have primarily focused on the infiltrating immune cell populations or the intricate HCC ecosystem [11][12][13]. There is still an open question regarding the interaction between CSCs and TAMs in HCC.…”

Section: Introductionmentioning

confidence: 99%

Reciprocal interactions between malignant cells and macrophages enhance cancer stemness and M2 polarization in HBV-associated hepatocellular carcinoma

Zhang,

Tsui,

Zhang

et al. 2024

Theranostics

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Background:The tumor microenvironment of cancers has emerged as a crucial component in regulating cancer stemness and plays a pivotal role in cell-cell communication. However, the specific mechanisms underlying these phenomena remain poorly understood. Methods: We performed the single-cell RNA sequencing (scRNA-seq) on nine HBV-associated hepatocellular carcinoma (HCC) patients. The heterogeneity of the malignant cells in pathway functions, transcription factors (TFs) regulation, overall survival, stemness, as well as ligand-receptor-based intercellular communication with macrophages were characterized. The aggressive and stemness feature for the target tumor subclone was validated by the conduction of in vitro assays including sphere formation, proliferation, Annexin V apoptosis, flow cytometry, siRNA library screening assays, and multiple in vivo preclinical mouse models including mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection. Results: Our analysis yielded a comprehensive atlas of 31,664 cells, revealing a diverse array of malignant cell subpopulations. Notably, we identified a stemness-related subclone of HCC cells with concurrent upregulation of CD24, CD47, and ICAM1 expression that correlated with poorer overall survival. Functional characterization both in vitro and in vivo validated S100A11 as one of the top downstream mediators for tumor initiation and stemness maintenance of this subclone. Further investigation of cell-cell communication within the tumor microenvironment revealed a propensity for bi-directional crosstalk between this stemness-related subclone and tumor-associated macrophages (TAMs). Co-culture study showed that this interaction resulted in the maintenance of the expression of cancer stem cell markers and driving M2-like TAM polarization towards a pro-tumorigenic niche. We also consolidated an inverse relationship between the proportions of TAMs and tumor-infiltrating T cells. Conclusions: Our study highlighted the critical role of stemness-related cancer cell populations in driving an immunosuppressive tumor microenvironment and identified the S100A11 gene as a key mediator for stemness maintenance in HCC. Moreover, our study provides support that the maintenance of cancer stemness is more attributed to M2 polarization than the recruitment of the TAMs.

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“…Given that HCC is a highly heterogeneous tumor ( 7 , 8 ), some relatively weak yet important signals on glycolytic signaling pathways in the liver may be missed by conventional sequencing techniques. Single-cell RNA sequencing analysis (scRNA-Seq) is an excellent technique used to explore the genetic information in specific cell clusters in tumor tissues of a patient ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Combining a glycolysis‑related prognostic model based on scRNA‑Seq with experimental verification identifies ZFP41 as a potential prognostic biomarker for HCC

Teng,

Xu,

Wang

et al. 2024

Mol Med Rep

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Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis, and its heterogeneity affects the response to clinical treatments. Glycolysis is highly associated with HCC therapy and prognosis. The present study aimed to identify a novel biomarker for HCC by exploring the heterogeneity of glycolysis in HCC. The intersection of both marker genes of glycolysis-related cell clusters from single-cell RNA sequencing analysis and mRNA data of liver HCC from The Cancer Genome Atlas were used to construct a prognostic model through Cox proportional hazard regression and the least absolute shrinkage and selection operator Cox regression. Data from the International Cancer Genome Consortium were used to validate the results of the analysis. Immune status analysis was then conducted. A significant gene in the prognostic model was identified as a potential biomarker and was verified through in vitro experiments. The results revealed that the glycolysis-related prognostic model divided patients with HCC into high- and low-risk groups. A nomogram combining the model and clinical features exhibited accurate predictive ability, with an area under the curve of 0.763 at 3 years. The high-risk group exhibited a higher expression of checkpoint genes and lower tumor immune dysfunction and exclusion scores, suggesting that this group may be more likely to benefit from immunotherapy. The tumor tissues had a higher zinc finger protein (ZFP)41 mRNA and protein expression compared with the adjacent tissues. In vitro analyses revealed that ZFP41 played a crucial role in cell viability, proliferation, migration, invasion and glycolysis. On the whole, the present study demonstrates that the glycolysis-related prognostic gene, ZFP41, is a potential prognostic biomarker and therapeutic target, and may play a crucial role in glycolysis and malignancy in HCC.

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Single-Cell Transcriptomics of Liver Cancer: Hype or Insights?

Cited by 9 publications

References 66 publications

Unveiling the Dual Expression of Haptoglobin in Malignant Hepatocellular Carcinoma Cells through Single-Cell and Bulk RNA Sequencing Analysis

Unveiling the Dual Expression of Haptoglobin in Malignant Hepatocellular Carcinoma Cells through Single-Cell and Bulk RNA Sequencing Analysis

Reciprocal interactions between malignant cells and macrophages enhance cancer stemness and M2 polarization in HBV-associated hepatocellular carcinoma

Combining a glycolysis‑related prognostic model based on scRNA‑Seq with experimental verification identifies ZFP41 as a potential prognostic biomarker for HCC

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