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Methionine synthase supports tumour tetrahydrofolate pools

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Abstract

Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that MTR is only a minor source of methionine in cell culture, tissues or xenografted tumours. Instead, MTR is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumour cells leads to folate trapping, purine synthesis stalling, nucleotide depletion and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating THF for use in one-carbon metabolism.

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Fig. 1: MTR is a minor source of methionine in cell lines, tissues and tumours.
Fig. 2: MTR is essential for cell and tumour growth under physiological folate conditions.
Fig. 3: Loss of MTR results in the elevation of 5-methyl-THF and depletion of other folate species.
Fig. 4: MTR supports purine biosynthesis by promoting folate availability.

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Data availability

Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author on request.

Code availability

The ‘Accucor’ package for natural isotope correction is publicly available through GitHub (https://github.com/lparsons/accucor).

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Acknowledgements

We thank W. Lu and other members of the Rabinowitz laboratory for helpful comments and suggestions. LentiCRISPR v.2 was a gift from F. Zhang (Addgene plasmid no. 52961). This work was supported by National Institutes of Health grant nos. 1DP1DK113643 and R01 CA163591 to J.D.R.

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Author notes

  1. Jonathan M. Ghergurovich

    Present address: The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

  2. These authors contributed equally: Jonathan M. Ghergurovich, Xincheng Xu, Joshua Z. Wang.

Authors and Affiliations

  1. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

    Jonathan M. Ghergurovich, Xincheng Xu, Joshua Z. Wang, Lifeng Yang, Rolf-Peter Ryseck, Lin Wang & Joshua D. Rabinowitz

  2. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Jonathan M. Ghergurovich & Lifeng Yang

  3. Department of Chemistry, Princeton University, Princeton, NJ, USA

    Xincheng Xu, Joshua Z. Wang, Lin Wang & Joshua D. Rabinowitz

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Contributions

J.M.G. conceived the study. J.M.G., X.X., J.Z.W. and J.D.R. designed the experiments. J.Z.W., X.X., J.M.G., L.Y., R.-P.R. and L.W. conducted the experiments. J.Z.W., X.X., J.M.G. and J.D.R. wrote the paper with input from the other authors.

Corresponding author

Correspondence to Joshua D. Rabinowitz.

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Competing interests

J.D.R. is a paid adviser and stockholder in Kadmon Pharmaceuticals, L.E.A.F. Pharmaceuticals and Rafael Pharmaceuticals; a paid consultant of Pfizer; a founder, director, and stockholder of Farber Partners and Serien Therapeutics. J.D.R. and J.M.G. are inventors of patents in the area of folate metabolism held by Princeton University. The other authors declare no competing interests.

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Peer review information Nature Metabolism thanks Kivanc Birsoy, Jason Locasale and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: George Caputa.

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Extended data

Extended Data Fig. 1 MTR is a minor source of methionine in vitro and in vivo.

(a) Schematic of methionine labeling from [U-13C]methionine. Red circles indicate 13C atoms. MTR = methionine synthase. (b) Schematic of methionine labeling from [U-13C] or [3-13C]serine. Blue circles indicate 13C atoms. MTHFR = methylenetetrahydrofolate reductase, SHMT = serine hydroxymethyltransferase. (c) Methionine labeling in cell lines after culturing for 4 h in media containing [U-13C]serine (for 293 T) or [3-13C]serine (for HCT116 and HepG2) (mean ± SD, n = 2). (d) Methionine M + 1 fraction from 4 h [3-13C]serine tracing in HCT116 cultured in media containing indicated methionine and folate concentrations (mean ± SD, n = 3 for each condition). Labeling of (e) serine and (f) methionine in serum, PDAC tumors, and normal tissues of male C57BL/6 mice after [U-13C]serine infusion for 2.5 h. (mean ± SD, n = 3 mice; two technical replicates were included for each tumour). (g) Schematic of methionine labeling from [13C5,15N]betaine. Orange circles indicate 13C atoms, green circles indicate 15N atoms. BHMT = betaine-homocysteine S-methyltransferase, DMG = dimethylglycine.

Source data

Extended Data Fig. 2 MTR is important for cell growth in physiological folates.

(a) Expression of MTR in the HCT116, 8988 T, and HepG2 cell lines as reported in the Cancer Cell Line Encyclopedia.63 (b) Cell growth curves in the media containing indicated folate sources (mean ± SD, n = 2). (c) Cell growth curves in media containing indicated folate and methionine concentrations (mean ± SD, n = 3). (d) Individual tumor volumes for HCT116 xenografts in female CD-1 nude mice (n = 10 mice). (e) Terminal tumor mass of HCT116 xenografts in female CD-1 nude mice (mean ± SEM, n = 10 mice). P values were determined by a two-sided paired Student’s t-test comparing ΔMTR-1 to wild-type, and ΔMTR-2 to CRISPR control (control-1). (f) Growth of subcutaneous HCT116 xenografts in male CD-1 nude mice on a standard folate (4ppm) or low folate diet (mean ± SEM, n = 10 mice). (g) Western blot analysis of MTR and eGFP in HCT116 wild-type (WT), CRISPR control-1 or ΔMTR-1 which was also engineered to express a vector containing either eGFP or MTR cDNA. Loading control (COXIV) was analyzed on a separate gel from parallel experiments. Results are representative of 2 independent biological replicates with similar results. SI = small intestine, SM = skeletal muscle.

Source data

Extended Data Fig. 3 Loss of MTR disrupts nucleotide synthesis.

(a) Water-soluble metabolite levels from HCT116 control and MTR knockout cells cultured in indicated media conditions. Each box reflects one independent biological measurement, normalized to the average of control cells cultured in folic acid. (b) Relative nucleotide mono- and diphosphate abundances in HCT116 control and MTR knockout cells in indicated media. Intensities are normalized to the average of control-1 cells in folic acid (mean ± SD, n = 3). (c) Relative thymidylate species abundances in HCT116 control and knockout cells in indicated media. Intensities are normalized to the average of control-1 cells in folic acid (mean ± SD, n = 3). (d) Cell growth dose response curves for HCT116 WT and MTR knockout cells treated with SHMT1/2 inhibitor SHIN2 under different folate conditions (mean ± SD, n = 5). For (B) and (C), P values were determined by a one-way ANOVA comparing control to MTR knockout in the same medium followed by Dunnett’s post hoc analysis.

Source data

Extended Data Fig. 4 Metabolomics of MTR knockout tumors.

(a) Water-soluble metabolites levels from individual HCT116 control and MTR knockout subcutaneous tumors (normalized to wild-type tumor average). (b) Relative abundance of an S-ribosylhomocysteine isomer in HCT116 control and MTR knockout subcutaneous tumors (mean ± SD, n = 10 tumors for control-1, and n = 9 tumors for each other group). Mice were fed standard chow. (c) MS/MS spectrum of m/z 268.0848 peak in positive-ion mode. Fragmentation pattern suggests an S-ribosylhomocysteine (SRH) isomer. WT = wild-type.

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Ghergurovich, J.M., Xu, X., Wang, J.Z. et al. Methionine synthase supports tumour tetrahydrofolate pools. Nat Metab 3, 1512–1520 (2021). https://doi.org/10.1038/s42255-021-00465-w

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