Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer.

Josep Tarragó-Celada,Pedro De Atauri,Míriam Tarrado-Castellarnau,Silvia Marin,Roger R Gomis,Eytan Ruppin,Xavier Hernández-Alias,David Hockenbery,Marta Cascante,Carles Foguet,Fionnuala Morrish,Jordi Perarnau,Mariia Yuneva

doi:10.3390/cancers13030425

Abstract

Simple SummaryIn 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.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.

Highlights

Colorectal cancer is the second leading cause of cancer mortality with over 800,000 deaths per year [1]
To gain better understanding of the metabolic phenotype associated with metastatic potential in colon cancer, we used cell lines differing in malignancy potential and characterised their growth, expression of metabolic modulators, invasion and tumorigenic capacities
Increased proliferation in metastatic cell lines was correlated with increased MYC protein levels, while P-AKT levels were similar in the three cell lines (Figure 1b, Figure S1b,c)

Summary

Introduction

Colorectal cancer is the second leading cause of cancer mortality with over 800,000 deaths per year [1]. Surgery is usually the primary treatment and is successful in approximately 50% of patients [2]. Disease recurrence after surgery involving distant metastasis, frequently in the liver, is a major problem and is often the ultimate cause of death [3]. Only 25% of colorectal cancer patients with isolated liver metastasis benefit from a multimodal treatment including surgery. With current therapies, the 5-yearsurvival rate of patients with metastatic colorectal cancer (mCRC) is less than 10% [4]. It is of paramount importance to develop effective therapeutic strategies against colorectal cancer metastasis

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