Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer

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...

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Published inCancers Vol. 13; no. 3; p. 425
Main Authors Tarragó-Celada, Josep, Foguet, Carles, Tarrado-Castellarnau, Míriam, Marin, Silvia, Hernández-Alias, Xavier, Perarnau, Jordi, Morrish, Fionnuala, Hockenbery, David, Gomis, Roger R., Ruppin, Eytan, Yuneva, Mariia, Atauri, Pedro de, Cascante, Marta
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 23.01.2021
MDPI
Subjects
Adaptation
Adenocarcinoma
Cell growth
Colorectal cancer
Colorectal carcinoma
Dehydrogenases
Folic acid
Gene expression
Genotype & phenotype
Glucose
Homeostasis
Liver
Lymph nodes
Metabolism
Metabolites
Metastases
Metastasis
Patients
Polyamines
Proteins
Surgery
Therapeutic applications
Tumor cell lines
Vitamin B
genome-scale metabolic models
redox metabolism
colorectal cancer
metastasis
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Summary: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.
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These authors contributed equally.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13030425