Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma
Open accessAbstract
Background and aims The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity. Methods By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo. Results Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes. Conclusions This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
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CTNNB1 or MYC alone was insufficient to drive cancer within 4 weeks.
“CTNNB1 or MYC alone was insufficient to drive cancer within 4 weeks (38), but delivering both led to carcinogenesis within 1 to 2 weeks on the FVB strain background.”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [38]
The Results section (‘In vivo screen identifies cooperating driver genes in HCC’; page unavailable) reports that individual genetic alterations were not associated with mortality within eight months and that two drivers were required for efficient liver tumorigenesis in C57BL/6 mice. It does not establish that CTNNB1 or MYC alone failed to produce cancer specifically within four weeks; mortality is not the same measure as tumor formation. (LLM, conf=0.82)
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Cites
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- Authors
- Molina-Sánchez, P., Ruiz de Galarreta, M., Yao, M. A., Lindblad, K. E., Bresnahan, E., Bitterman, E., Martin, T. C., Rubenstein, T., Nie, K., Golas, J., Choudhary, S., Bárcena-Varela, M., Elmas, A., Miguela, V., Ding, Y., Kan, Z., Grinspan, L. T., Huang, K.-L., Parsons, R. E., Shields, D. J., Rollins, R. A., & Lujambio, A.
- Affiliations
- Tisch Cancer Institute (US)
- Pfizer (United States) (US)
- Corresponding author
- Shields, David J.
- Rollins, Robert A.
- Lujambio, Amaia
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 159
- Issue
- 6
- Pages
- 2203-2220.e14
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC7726023
- OpenAlex
- W3049585391
- Cited by
- 117
- References
- 5
- Citations by year
- 2026: 22 · 2025: 24 · 2024: 26 · 2023: 21 · 2022: 11 · 2021: 13
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Gastroenterology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- Pfizer
- Asociación Española para el Estudio del Hígado
- U.S. Department of Defense
- Philippe Foundation
- Fundación Alfonso Martín Escudero
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- hepatocellular carcinoma, intertumoral heterogeneity, cancer driver genes, c-Myc, β-catenin, oncogene cooperation, mouse tumor model, hydrodynamic injection, tumor immune microenvironment, tumor transcriptome, drug response, personalized treatment
- MeSH terms
- Animals, Disease Models, Animal, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Mice, Transgenic, Proto-Oncogenes, Gene Expression Regulation, Neoplastic, Genetic Heterogeneity, Drug Resistance, Neoplasm, Tumor Escape, Computational Biology, Cell Line, Tumor, Mice, Tumor Microenvironment
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