MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer
Abstract
Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.
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Many murine liver cancer models enforce oncogene or tumor suppressor perturbations in all hepatocytes or use mutagens that humans are rarely exposed to.
“Because many murine liver cancer models enforce oncogene or tumor suppressor perturbations in all hepatocytes or use mutagens that humans are rarely exposed to (20, 21), one cannot solely depend on these models to identify the cell of origin or to track the evolution of HCCs.”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [20]
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- Authors
- Shachaf, C. M., Kopelman, A. M., Arvanitis, C., Karlsson, Å., Beer, S., Mandl, S., Bachmann, M. H., Borowsky, A. D., Ruebner, B., Cardiff, R. D., Yang, Q., Bishop, J. M., Contag, C. H., & Felsher, D. W.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- University of California Davis Medical Center (US)
- University of California, San Francisco (US)
- Corresponding author
- Felsher, Dean W.
- ORCID
- Venue
- Nature
- Published
- 2004-10
- Volume
- 431
- Issue
- 7012
- Pages
- 1112-1117
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2054657650
- Cited by
- 874
- References
- 1
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 26 · 2023: 40 · 2022: 41 · 2021: 43 · 2020: 42 · 2019: 38 · 2018: 35 · 2017: 45 · 2016: 43 · 2015: 30 · 2014: 41 · 2013: 51 · 2012: 41
- FWCI
- 20.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- hepatocellular carcinoma, tumor dormancy, tumor differentiation, hepatocyte differentiation, biliary differentiation, alpha-fetoprotein, cytokeratin 19, liver stem cells, clonal origin, tumor regression
- MeSH terms
- Animals, Bile Ducts, Cell Differentiation, Cell Transformation, Neoplastic, Carcinoma, Hepatocellular, Luminescent Measurements, Mice, Transgenic, Stem Cells, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Genes, myc, Proto-Oncogene Proteins c-myc, Mice, SCID, Apoptosis, Mice
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