Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer
Abstract
Simple Summary
Abstract
1. Introduction
2. Results
2.1. Characterisation of the Metastatic Phenotype
2.2. The metastatic Cell Lines Display Increased Glucose, Glutamine and Mitochondrial Metabolism
2.3. The Metabolic Adaptation of the Metastatic Cell Lines Observed In Vitro Is Maintained in an In Vivo Scenario
2.4. Computational Inference of Cell Line-Specific Metabolic Flux Maps and Metabolic Targets through Multiomics Data Integration
2.5. Metastatic Cell Lines Are Dependent on Cysteine Uptake and Vulnerable to System xCT and Glutathione Reductase Inhibition
2.6. The Metastatic Cell Lines Are Vulnerable to Inhibition of Folate Metabolism
2.7. Synergistic Effect of the Simultaneous Inhibition of Cysteine Uptake and Folate Metabolism
3. Discussion
4. Materials and Methods
4.1. Cell Lines and Culture
4.2. Chemicals
4.3. Xenograft Experiments
4.4. Cell Proliferation Assay Using Fluorospheres
4.5. IC50 Curve Determination Using Hoechst
4.6. Apoptosis Assay
4.7. Spheroids Assays
4.8. Wound Healing Assay
4.9. Western Blotting
4.10. Immunohistochemistry
4.11. Spectrophotometric Measurements
4.12. OCR Measurements, Mito Stress and Mito Fuel Assays
4.13. Targeted Metabolomics
4.14. Stable Isotope-Resolved Metabolomics In Vitro
4.15. Stable Isotope-Resolved Metabolomics In Vivo
4.16. Statistical Analyses
4.17. Multiomics Data Integration
4.18. Identifying Putative Metabolic Targets
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene KO(s) | Predicted Fraction of Growth Compared to Wild Type | |||
---|---|---|---|---|
SW480 | SW620 | LiM2 | ||
Single Targets | MTHFD1 | 100% | 0% | 0% |
GSR | 99% | 0% | 0% | |
Target Pairs | SLC7A9, SLC3A2 | 86% | 0% | 0% |
SLC3A1, SLC3A2 | 86% | 0% | 0% | |
SLC7A9, SLC7A11 | 85% | 0% | 0% | |
SLC7A11, SLC3A1 | 85% | 0% | 0% |
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Tarragó-Celada, J.; Foguet, C.; Tarrado-Castellarnau, M.; Marin, S.; Hernández-Alias, X.; Perarnau, J.; Morrish, F.; Hockenbery, D.; Gomis, R.R.; Ruppin, E.; et al. Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer. Cancers 2021, 13, 425. https://doi.org/10.3390/cancers13030425
Tarragó-Celada J, Foguet C, Tarrado-Castellarnau M, Marin S, Hernández-Alias X, Perarnau J, Morrish F, Hockenbery D, Gomis RR, Ruppin E, et al. Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer. Cancers. 2021; 13(3):425. https://doi.org/10.3390/cancers13030425
Chicago/Turabian StyleTarragó-Celada, Josep, Carles Foguet, Míriam Tarrado-Castellarnau, Silvia Marin, Xavier Hernández-Alias, Jordi Perarnau, Fionnuala Morrish, David Hockenbery, Roger R. Gomis, Eytan Ruppin, and et al. 2021. "Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer" Cancers 13, no. 3: 425. https://doi.org/10.3390/cancers13030425
APA StyleTarragó-Celada, J., Foguet, C., Tarrado-Castellarnau, M., Marin, S., Hernández-Alias, X., Perarnau, J., Morrish, F., Hockenbery, D., Gomis, R. R., Ruppin, E., Yuneva, M., Atauri, P. d., & Cascante, M. (2021). Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer. Cancers, 13(3), 425. https://doi.org/10.3390/cancers13030425