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Simple Summary  In this work, we studied the metabolic reprogramming of same-patient-derived cell lines with increasing metastatic potential to develop new therapeutic approaches against metastatic colorectal cancer. Using a novel systems biology approach to integrate multiple layers of omics data, we predicted and validated that cystine uptake and folate metabolism, two key pathways related to redox metabolism, are potential targets against metastatic colorectal cancer. Our findings indicate that metastatic cell lines are selectively dependent on redox homeostasis, paving the way for new targeted therapies.    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.

Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer