ArticleJournal of hepatology2023
MYC determines lineage commitment in KRAS-driven primary liver cancer development.
Article in Journal of hepatology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 32 citations in OpenAlex.
- KPT-330-mediated XPO1 inhibition impairs homologous recombination and enhances radiosensitivity in extranodal NK/T-cell lymphoma.British journal of cancer · 2026Article
- Co-repression of Yap1 and Sox9 abrogates established cholangiocarcinoma by eliminating transcriptional compensation.Clinical and molecular hepatology · 2026Article
- KRAS and MYC synergistic inhibition: a powerful strategy targeting KRAS-mutant cancers.Molecular cancer · 2026Review
- RNA helicase SKIV2L impedes tumor immunity by reprogramming arginine metabolism of hepatocellular carcinomas.Journal for immunotherapy of cancer · 2026Article
- How to efficiently establish animal models of cholangiocarcinoma: challenges and inspiration.Medical review (2021) · 2026Review
- PVT1-104aa derived from the 8q24 gene desert promotes colorectal cancer tumorigenesis.Clinical and translational medicine · 2026Article
- Co-repression ofbioRxiv : the preprint server for biology · 2026Article
- Functional Difference of MYC and MYCN in Combined Hepatocellular-Cholangiocarcinoma: Regulation of Differentiation by HNF1B.Cancer science · 2026Article
- Review
- KBTBD11 suppresses hepatocellular carcinoma by targeting ENO1-mediated glycolysis.Journal of translational medicine · 2025Article
- CRISPR screening reveals that RNA helicase DDX41 triggers ribosome biogenesis and cancer progression through R-loop-mediated RPL/RPS transcription.Nature communications · 2025Article
- The rise of RAS: how gradual oncogene activation shapes the OIS spectrum.Genes & development · 2025Review
- Immunometabolic Targets in CD8Liver cancer · 2025Review
- Hepatic factor MANF drives hepatocytes reprogramming by detaining cytosolic CK19 in intrahepatic cholangiocarcinoma.Cell death and differentiation · 2025Article
- Targeting KRAS Sensitizes Ferroptosis by Coordinately Regulating the TCA Cycle and Nrf2-SLC7A11-GPX4 Signaling in Hepatocellular Carcinoma.Smart medicine · 2025Article
- Bisphenol S Exposure and MASLD: A Mechanistic Study in Mice.Environmental health perspectives · 2025Article
- Retracted: ATT-Myc Transgenic Mouse Model and Gene Expression Identify Genotoxic and Non-Genotoxic Chemicals That Accelerating Liver Tumor Growth in Short-Term Toxicity.Biomedicines · 2025Article
- Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma.The American journal of pathology · 2025Review
- RIT1 Promotes the Proliferation of Gliomas Through the Regulation of the PI3K/AKT/c-Myc Signalling Pathway.Journal of cellular and molecular medicine · 2025Article
- MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer.Signal transduction and targeted therapy · 2024Review
Corrections and comments
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Authors and funding
20 authors at 8 institutions in 4 countries.
Funding
Abstract
BACKGROUND &
aimsPrimary liver cancer (PLC) comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their tumour biology and responses to cancer therapies. Liver cells harbour a high degree of cellular plasticity and can give rise to either HCC or iCCA. However, little is known about the cell-intrinsic mechanisms directing an oncogenically transformed liver cell to either HCC or iCCA. The scope of this study was to identify cell-intrinsic factors determining lineage commitment in PLC.
methodsCross-species transcriptomic and epigenetic profiling was applied to murine HCCs and iCCAs and to two human PLC cohorts. Integrative data analysis comprised epigenetic Landscape In Silico deletion Analysis (LISA) of transcriptomic data and Hypergeometric Optimization of Motif EnRichment (HOMER) analysis of chromatin accessibility data. Identified candidate genes were subjected to functional genetic testing in non-germline genetically engineered PLC mouse models (shRNAmir knockdown or overexpression of full-length cDNAs).
resultsIntegrative bioinformatic analyses of transcriptomic and epigenetic data pinpointed the Forkhead-family transcription factors FOXA1 and FOXA2 as MYC-dependent determination factors of the HCC lineage. Conversely, the ETS family transcription factor ETS1 was identified as a determinant of the iCCA lineage, which was found to be suppressed by MYC during HCC development. Strikingly, shRNA-mediated suppression of FOXA1 and FOXA2 with concomitant ETS1 expression fully switched HCC to iCCA development in PLC mouse models.
conclusionsThe herein reported data establish MYC as a key determinant of lineage commitment in PLC and provide a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. IMPACT AND IMPLICATIONS: Liver cancer is a major health problem and comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their morphology, tumour biology, and responses to cancer therapies. We identified the transcription factor and oncogenic master regulator MYC as a switch between HCC and iCCA development. When MYC levels are high at the time point when a hepatocyte becomes a tumour cell, an HCC is growing out. Conversely, if MYC levels are low at this time point, the result is the outgrowth of an iCCA. Our study provides a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. Furthermore, our data harbour potential for the development of better PLC therapies.
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