The landscape of cancer cell line metabolism

Abstract

Despite considerable efforts to identify cancer metabolic alterations that might unveil druggable vulnerabilities, systematic characterizations of metabolism as it relates to functional genomic features and associated dependencies remain uncommon. To further understand the metabolic diversity in cancer, we profiled 225 metabolites in 928 cell lines from more than 20 cancer types in the Cancer Cell Line Encyclopedia (CCLE) using liquid chromatography-mass spectrometry (LC-MS). This resource enables unbiased association analysis linking cancer metabolome to genetic alterations, epigenetic features, and gene dependencies. Additionally, by screening barcoded cell lines, we demonstrated that aberrant ASNS hypermethylation sensitizes subsets of gastric and hepatic cancers to asparaginase therapy. Finally, our analysis revealed distinct synthesis and secretion patterns of kynurenine, an immune-suppressive metabolite, in model cancer cell lines. Together, these findings and related methodology provide comprehensive resources that will help to clarify the landscape of cancer metabolism.

SLC 1A3 contributes to L‐asparaginase resistance in solid tumors

“…ASNase could break down both asparagine and glutamine, even though its glutaminase activity was not required for ASNS‐negative cancer cells (Chan et al , ). Moreover, ASNase was found effective in treating solid tumors with intrinsic loss of ASNS (Li et al , ). We observed that in cell culture conditions, both asparagine and glutamine were robustly depleted by ASNase (Fig G).…”

Fat for fuel: lipid metabolism in haematopoiesis

“…As such, the global lipid landscape of cancer cell lines greatly differs from noncancerous cells . Indeed, recent evidence also shows that substantial lipid diversity exists within distinct types of cancer cells …”

“…91 Indeed, recent evidence also shows that substantial lipid diversity exists within distinct types of cancer cells. 92 Sphingolipid synthesis is a tightly regulated process that is thought to be self-regulated. Importantly, enzymes involved in sphingolipid metabolism have been identified as targets for the Runx family of genes with glucosylceramide and ganglioside synthesis being upregulated and S1P catabolism downregulated upon Runx activation.…”

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

“…The inherent plasticity of cellular metabolism and the high degree of metabolic heterogeneity in TNBCs pose great challenges for metabolism targeting therapy 21 . Recent work suggests that heterogeneous metabolic dependencies within cancer cells underline the differential therapeutic vulnerabilities 22 . Therefore, in order for GLUT1 inhibition to be a successful strategy for TNBC therapy, the precise contexts in which this metabolic pathway is essential needs to be identified.…”