As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues1,2, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS3,4, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function5. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.
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We thank G. Stephanopoulos for assistance with Nutrostat design, M. Holland for mtDNA sequencing consultation, L. Garraway for assistance identifying mtDNA mutant cell lines, T. Yagi for the NDI1 antibody, T. DiCesare for diagrams, and members of the Sabatini Laboratory for assistance (particularly A. Saucedo, C. Koch, O. Yilmaz, Y. Gultekin and A. Hutchins for technical assistance, and D. Lamming and W. Comb for critical reading of the manuscript). This research is supported by fellowships from The Leukemia and Lymphoma Society and The Jane Coffin Childs Fund to K.B., the Council of Higher Education Turkey and Karadeniz T. University Scholarships to B.Y. and grants from the David H. Koch Institute for Integrative Cancer Research at MIT, The Alexander and Margaret Stewart Trust Fund, the NIH (K99 CA168940 to R.P. and CA103866, CA129105, and AI07389 to D.M.S.) and the Starr Cancer Consortium. D.M.S. is an investigator of the Howard Hughes Medical Institute.
Extended data figures
Primary Cell Competition Data. Primary Data for Figure 2b, Proliferation of barcoded cell lines in high and low glucose.
Primary Screening Data. Primary Data for Figure 2d, RNAi Screen under 10 mM or 0.75 mM glucose conditions.
Alternative Hit Lists from Pooled shRNA Screen. Data from Supplementary Table 2 analyzed using the GENE-E software to generate lists of scoring genes alternative to those in Figure 2e and Extended Data Figure 2a.
Impaired Glucose Import Gene Signature Data. Primary Data for Extended Data Figure 5.