Cysteine and folate metabolism are targetable vulnerabilities of metastatic colorectal cancerMore about Open Access at the Crick
Authors listJosep Tarragó-Celada Carles Foguet Míriam Tarrado-Castellarnau Silvia Marin Xavier Hernández-Alias Jordi Perarnau Fionnuala Morrish David Hockenbery Roger R Gomis Eytan Ruppin Mariia Yuneva Pedro de Atauri Marta Cascante
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.
Issue number 3