2. Academic Validation
  3. Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer

Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer

  • Cancers (Basel). 2021 Jan 23;13(3):425. doi: 10.3390/cancers13030425.
Josep Tarragó-Celada 1,  Carles Foguet 1 2,  Míriam Tarrado-Castellarnau 1 2,  Silvia Marin 1 2,  Xavier Hernández-Alias 1 3,  Jordi Perarnau 1,  Fionnuala Morrish 3,  David Hockenbery 3,  Roger R Gomis 4 5 6 7,  Eytan Ruppin 8,  Mariia Yuneva 9,  Pedro de Atauri 1 2,  Marta Cascante 1 2 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biomedicine & Institute of Biomedicine of Universitat de Barcelona, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain.
  • 2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) and Metabolomics Node at Spanish National Bioinformatics Institute (INB-ISCIII-ES-ELIXIR), Instituto de Salud Carlos III (ISCIII), 28020 Madrid, Spain.
  • 3 Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • 4 ICREA, 08010 Barcelona, Spain.
  • 5 Institute for Research in Biomedicine Barcelona (IRB Barcelona) and The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
  • 6 CIBERONC, Instituto de Salud Carlos III (ISCIII), 28020 Madrid, Spain.
  • 7 Department of Medicine, Faculty of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain.
  • 8 Center for Cancer Research, Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD 20892, USA.
  • 9 Oncogenes and Tumour Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
PMID: 33498690 DOI: 10.3390/cancers13030425
Abstract

With most cancer-related deaths resulting from metastasis, the development of new therapeutic approaches against metastatic colorectal Cancer (mCRC) is essential to increasing patient survival. The metabolic adaptations that support mCRC remain undefined and their elucidation is crucial to identify potential therapeutic targets. Here, we employed a strategy for the rational identification of targetable metabolic vulnerabilities. This strategy involved first a thorough metabolic characterisation of same-patient-derived cell lines from primary colon adenocarcinoma (SW480), its lymph node metastasis (SW620) and a liver metastatic derivative (SW620-LiM2), and second, using a novel multi-omics integration workflow, identification of metabolic vulnerabilities specific to the metastatic cell lines. We discovered that the metastatic cell lines are selectively vulnerable to the inhibition of cystine import and folate metabolism, two key pathways in redox homeostasis. Specifically, we identified the system xCT and MTHFD1 genes as potential therapeutic targets, both individually and combined, for combating mCRC.

Keywords

colorectal cancer; genome-scale metabolic models; metastasis; redox metabolism.

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