TPO-Induced Metabolic Reprogramming Drives Liver Metastasis of Colorectal Cancer CD110+ Tumor-Initiating Cells
Open accessAbstract
Liver metastasis is a leading cause of death in patients with colorectal cancer. We previously found that colorectal cancer tumor-initiating cells (TICs) expressing CD110, the thrombopoietin (TPO)-binding receptor, mediate liver metastasis. Here, we show that TPO promotes metastasis of CD110+ TICs to the liver by activating lysine degradation. Lysine catabolism generates acetyl-CoA, which is used in p300-dependent LRP6 acetylation. This triggers tyrosine phosphorylation of LRP6, ultimately activating Wnt signaling to promote self-renewal of CD110+ TICs. Lysine catabolism also generates glutamate, which modulates the redox status of CD110+ TICs to promote liver colonization and drug resistance. Mechanistically, TPO-mediated induction of c-myc orchestrates recruitment of chromatin modifiers to regulate metabolic gene expression. Our findings, therefore, establish TPO as a component of the physiological environment critical for metastasis of colorectal cancer to the liver.
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Inhibition of class I HDACs is associated with activation of Wnt/β-catenin signaling.
“It has been demonstrated that inhibition of class I HDACs is associated with activation of Wnt/β-catenin signaling [42–47].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [43]
A growing body of evidence shows that inhibition of class I HDACs results in activation of Wnt/β-catenin signaling.
“A growing body of evidence shows that inhibition of class I HDACs results in activation of Wnt/β-catenin signaling.”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [43]
Acetylation of Wnt co-receptor LRP6 triggers LRP6 phosphorylation and Wnt/β-catenin signaling activation.
“Thirdly, the acetylation of Wnt co-receptor LRP6 triggers LRP6 phosphorylation and Wnt/β-catenin signaling activation [43]”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [43]
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References 39 · Cited by 149
- Authors
- Wu, Z., Wei, D., Gao, W., Xu, Y., Hu, Z., Ma, Z., Gao, C., Zhu, X., & Li, Q.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- People's Liberation Army No. 150 Hospital (CN)
- Second Military Medical University (CN)
- Fudan University (CN)
- Corresponding author
- Li, QingQuan
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 17
- Issue
- 1
- Pages
- 47-59
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W1594101637
- Cited by
- 149
- References
- 39
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 16 · 2023: 17 · 2022: 17 · 2021: 23 · 2020: 10 · 2019: 14 · 2018: 11 · 2017: 11 · 2016: 9 · 2015: 3
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- colorectal cancer, liver metastasis, cancer stem cells, thrombopoietin, lysine catabolism, acetyl-CoA, Wnt signaling, glutamate, redox state, drug resistance, c-Myc, chromatin modifiers, metabolic reprogramming, tumor self-renewal
- MeSH terms
- Acetyl Coenzyme A, Acetylation, Animals, Fatty Acids, Humans, Liver Neoplasms, Lysine, Thrombopoietin, Neoplastic Stem Cells, Colorectal Neoplasms, Genes, myc, Mice, Knockout, Oxidative Stress, Cell Line, Tumor, E1A-Associated p300 Protein, Mice, Receptors, Thrombopoietin, Low Density Lipoprotein Receptor-Related Protein-6, Heterografts, Cellular Reprogramming
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