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Single-Cell Analysis of Primary Liver Cancer in Mouse Models.

ABSTRACT: Primary liver cancer (PLC), consisting mainly of hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is one of the major causes of cancer-related mortality worldwide. The curative therapy for PLC is surgical resection and liver transplantation, but most PLCs are inoperable at diagnosis. Even after surgery, there is a high rate of tumor recurrence. There is an unmet clinical need to discover more effective treatment options for advanced PLCs. Pre-clinical mouse models in PLC research have played a critical role in identifying key oncogenic drivers and signaling pathways in hepatocarcinogenesis. Furthermore, recent advances in single-cell RNA sequencing (scRNA-seq) have provided an unprecedented degree of resolution in such characterization. In this review, we will summarize the recent studies that utilized pre-clinical mouse models with the combination of scRNA-seq to provide an understanding of different aspects of PLC. We will focus particularly on the potentially actionable targets regarding the cellular and molecular components. We anticipate that the findings in mouse models could complement those in patients. With more defined etiological background, mouse models may provide valuable insights.

SUBMITTER: Suoangbaji T

PROVIDER: S-EPMC9914042 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Single-Cell Analysis of Primary Liver Cancer in Mouse Models.

Suoangbaji Tina T Zhang Vanilla Xin VX Ng Irene Oi-Lin IO Ho Daniel Wai-Hung DW

Cells 20230201 3

Primary liver cancer (PLC), consisting mainly of hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is one of the major causes of cancer-related mortality worldwide. The curative therapy for PLC is surgical resection and liver transplantation, but most PLCs are inoperable at diagnosis. Even after surgery, there is a high rate of tumor recurrence. There is an unmet clinical need to discover more effective treatment options for advanced PLCs. Pre-clinical mouse models in PLC research ha ...[more]

PMID: 36766817

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Project description:Background & aimsHuman primary liver cancer is classified into biologically distinct subgroups based on cellular origin. Liver cancer stem cells (CSCs) have been recently described. We investigated the ability of distinct lineages of hepatic cells to become liver CSCs and the phenotypic and genetic heterogeneity of primary liver cancer.MethodsWe transduced mouse primary hepatic progenitor cells, lineage-committed hepatoblasts, and differentiated adult hepatocytes with transgenes encoding oncogenic H-Ras and SV40LT. The CSC properties of transduced cells and their ability to form tumors were tested by standard in vitro and in vivo assays and transcriptome profiling.ResultsIrrespective of origin, all transduced cells acquired markers of CSC/progenitor cells, side populations, and self-renewal capacity in vitro. They also formed a broad spectrum of liver tumors, ranging from cholangiocarcinoma to hepatocellular carcinoma, which resembled human liver tumors, based on genomic and histologic analyses. The tumor cells coexpressed hepatocyte (hepatocyte nuclear factor 4α), progenitor/biliary (keratin 19, epithelial cell adhesion molecule, A6), and mesenchymal (vimentin) markers and showed dysregulation of genes that control the epithelial-mesenchymal transition. Gene expression analyses could distinguish tumors of different cellular origin, indicating the contribution of lineage stage-dependent genetic changes to malignant transformation. Activation of c-Myc and its target genes was required to reprogram adult hepatocytes into CSCs and for tumors to develop. Stable knockdown of c-Myc in transformed adult hepatocytes reduced their CSC properties in vitro and suppressed growth of tumors in immunodeficient mice.ConclusionsAny cell type in the mouse hepatic lineage can undergo oncogenic reprogramming into a CSC by activating different cell type-specific pathways. Identification of common and cell of origin-specific phenotypic and genetic changes could provide new therapeutic targets for liver cancer.

Project description:PurposeTreatment for advanced gallbladder cancer (GBC) remains controversial, with various recommendations regarding the choice and combination of surgery and adjuvant therapy. The present article is targeting for the exploration of optimal treatment models for advanced GBC.MethodsAJCC (American Joint Committee on Cancer, 8th edition) stage III and stage IV GBC, were defined as advanced GBC. Patients with advanced GBC were identified using the Surveillance, Epidemiology, and End Results (SEER) database and departmental cohort. Because of the most representative, only gallbladder adenocarcinoma (GBAC) patients were selected. Based on their surgical status (No, Non-radical and Radical surgery), chemotherapy status (Chemotherapy, No chemotherapy), and radiotherapy status (Radiotherapy, No radiotherapy), treatment models were categorized. For the purposes of evaluating the treatment outcomes of various treatment models and determining the risk element for cancer-specific survival (CSS), Cox regression analysis was applied. Kaplan-Meier curves were used before and after adjusting for covariates, with log-rank tests used to analyze discrepancies between curves. Immunotherapy was analyzed using clinical data from departmental cohort. Finally, to compensate for the limitations of the database, a review examines the progress in treatment models for advanced GBC.Results5,154 patients aged over 18 years with solitary primary advanced GBC were identified from the SEER database. In advanced GBC patients, the treatment model has emerged as a significant prognostic factor. "Radical surgery + Chemotherapy + Radiotherapy" models maximally improved the CSS of advanced GBC before and after adjusting for covariates, while "No surgery + No chemotherapy + No radiotherapy" model had the lowest CSS. The present conclusions were supported even after subgroup analysis by AJCC stage. The efficacy of immunotherapy was demonstrated in the departmental cohort analysis. Additionally, this article provides a comprehensive overview of recent advancements in various emerging treatment strategies.ConclusionEven when optimal treatment model cannot be pursued, providing comprehensive combinations of treatments to advanced GBC patients whenever possible is always beneficial for their survival.

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Single-Cell Analysis of Primary Liver Cancer in Mouse Models.

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Single-Cell Analysis of Primary Liver Cancer in Mouse Models.

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