Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer

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.

“Metabolic dysregulations of cancer cells with metastatic potential”

“…Dysregulated metabolism plays a vital role in cancer cell progression and metastasis [22,23,25,26,45–49]. In this study, we have shown that TNBC cell lines differentiating in their metastatic potential in vivo exhibit different metabolic profile already in vitro, and those differences are independent of the abundance of canonical EMT markers.…”

“…Nevertheless, we found increased level of citrate and molecules involved in citrate metabolism, which could suggest higher glucose contribution to TCA cycle in HMP cell lines. The greater flux of glucose into TCA cycle was recently reported in metastatic colorectal cancer cell lines [49]. The enhanced glycolysis along with intracellular accumulation of citrate were shown to enhance TNBC cell invasion and metastasis via AKT/ERK signaling pathway [46].…”

Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy

“…Transcriptomics and measured rates of metabolite uptake and secretions were integrated to the reconstructions using GIM 3 E [14] . GIM 3 E uses flux minimization weighted by transcriptomics Eq.…”

“…Case in point, a GSMM analysis of two isogenic prostate cancer cell lines identified that the cancer cell lines with cancer stem cell like phenotype were vulnerable to the accumulation of long-chain fatty acids with antiproliferative effects and could be selectively killed by blocking fatty acid oxidation [13] . Likewise, in a same patient-derived cell line panel, GSMMs have also enabled the identification that the combined inhibition of cystine uptake and folate metabolism is highly selective against metastatic cells [14] .…”

Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy

“…The first synthetic MTHFD1/2 inhibitor LY345899 has shown its anti-tumor activity in CRC [295]. Treatment of LY345899 led to reduced proliferative rate in primary CRC cells (SW480), its lymph node metastasis (SW620) and a liver metastatic derivative (SW620-LiM2), while no toxicity in the normal colon epithelial cells was observed [296]. In line with this, Ju et al found that LY345899 inhibited tumor growth and decreased the tumor weight in CRC patient-derived xenograft models without acute or delayed toxicity [297].…”