Single-cell transcriptomics reveals opposing roles of Shp2 in Myc-driven liver tumor cells and microenvironment
Open accessAbstract
The mechanisms of Myc-driven liver tumorigenesis are inadequately understood. Herein we show that Myc-driven hepatocellular carcinoma (HCC) is dramatically aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion. However, Myc-induced tumors develop selectively from the rare Shp2-positive hepatocytes in Shp2-deficent liver, and Myc-driven oncogenesis depends on an intact Ras-Erk signaling promoted by Shp2 to sustain Myc stability. Despite a stringent requirement of Shp2 cell autonomously, Shp2 deletion induces an immunosuppressive environment, resulting in defective clearance of tumor-initiating cells and aggressive tumor progression. The basal Wnt/β-catenin signaling is upregulated in Shp2-deficient liver, which is further augmented by Myc transfection. Ablating Ctnnb1 suppresses Myc-induced HCC in Shp2-deficient livers, revealing an essential role of β-catenin. Consistently, Myc overexpression and CTNNB1 mutations are frequently co-detected in HCC patients with poor prognosis. These data elucidate complex mechanisms of liver tumorigenesis driven by cell-intrinsic oncogenic signaling in cooperation with a tumor-promoting microenvironment generated by disrupting the specific oncogenic pathway.
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While our findings suggest that SHP2i and SOS1i may induce the same efficacy, inhibiting SOS1 avoids some of the pleiotropic effects of SHP2 inhibitors, potentially resulting in better clinical tolerability.
“Of note, while our findings suggest that SHP2i and SOS1i may induce the same efficacy, inhibiting SOS1 avoids some of the pleiotropic effects of SHP2 inhibitors56,57, potentially resulting in better clinical tolerability.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [56]
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Self-citation
- Authors
- Chen, W. S., Liang, Y., Zong, M., Liu, J. J., Kaneko, K., Hanley, K. L., Zhang, K., & Feng, G.-S.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Feng, Gen-Sheng
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 37
- Issue
- 6
- Pages
- 109974
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC8656042
- OpenAlex
- W3214255828
- Cited by
- 50
- References
- 67
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 13 · 2023: 20 · 2022: 9
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA236074, R01CA239629)
- National Institutes of Health (T32CA009523)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- SHP2, c-Myc, hepatocellular carcinoma, hepatocarcinogenesis, Ras/ERK signaling, tumor microenvironment, immunosuppression, Wnt/β-catenin signaling, β-catenin, CTNNB1, PTPN11, hepatocytes, tumor progression
- MeSH terms
- Animals, Carcinoma, Hepatocellular, Liver Neoplasms, Mice, Inbred C57BL, Mutation, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Mice, Knockout, Hepatocytes, beta Catenin, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Single-Cell Analysis, Tumor Microenvironment, Transcriptome, Wnt Signaling Pathway
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