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Modulating the therapeutic response of tumours to dietary serine and glycine starvation

A Corrigendum to this article was published on 03 August 2017

Abstract

The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis2,3,4, many others rely on exogenous serine for optimal growth5,6,7. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models7,8. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

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Figure 1: SG-free diet is an effective therapeutic intervention in GEMMs for lymphoma and intestinal cancer.
Figure 2: Manipulation of anti-oxidant response enhanced diet-induced anti-cancer effect.
Figure 3: Activated Kras confers resistance to the anti-cancer effects of SG-free diet.
Figure 4: Kras(G12D)-expressing cells resist SG starvation by upregulating de novo serine synthesis.

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Acknowledgements

We thank the BSU facilities at the CRUK Beatson Institute, C. Nixon, the histology facility and A. Hock for technical assistance, G. Kalna and R. Daly for advice on statistics and C. Winchester for reading the manuscript. We also thank R. DePinho for the Kras-inducible pancreatic cell lines. This work was funded by Cancer Research UK Grant C596/A10419, ERC Grant 322842-METABOp53 and a CRUK Career Development Fellowship (O.D.K.M.) C53309/A19702. O.S. and D.F.V. are funded by CRUK and an ERC Starting Grant (311301).

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Authors

Contributions

O.D.K.M. and K.H.V. conceived and designed the study. D.A., K.B., E.C.C., D.G., J.B., D.F.V. and O.J.S. performed/supervised GEMM/xenograft/allograft studies; D.A., K.B., O.D.K.M. and E.C.C. performed GEMM/xenograft/allograft data analysis. K.J.C. supplied cell lines and advised on allograft experiments. LC–MS was conducted by N.J.F.v.d.B., G.M.M., C.F.L. and T.Z. Metabolomics sample preparation and data analysis was performed by O.D.K.M. and T.Z. F.C. derived and cultured organoids; P.L. and E.C.C. cultured and analysed organoids; P.L. and O.D.K.M. cultured and analysed other cell lines. F.K. cultured cells and performed macropinocytosis assays and data analysis. The manuscript was written by O.D.K.M. and K.H.V.

Corresponding authors

Correspondence to Oliver D. K. Maddocks or Karen H. Vousden.

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Competing interests

K.H.V. is on the Science Advisory Board of Raze Therapeutics. O.D.K.M. and K.H.V. contributed to CRUK Cancer Research Technology filing of UK Patent Application no. 1609441.9.

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Reviewer Information Nature thanks I. Topisirovic and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Effect of SG-free diet on tumour burden in ApcMin/+ mice, and on serum glucose and lactate in ApcMin/+ and Eμ-Myc mice.

a, ApcMin/+ mice received normal chow until 80 days of age, then were transferred to either a control diet (containing SG) or a matched diet lacking serine and glycine (−SG) until clinical end point (intestinal-tumour-related survival). Post-mortem tumour measurement was performed on intestinal tissue at time of diet change (80 days) or clinical end point. P values calculated by t-test (unpaired, two-tailed, with correction for multiple comparisons). Diet-only tumour number data also shown in Fig. 2c. Diet-only tumour area data also shown in Extended Data Fig. 5b. See Source Data. b, ApcMin/+ and Eμ-Myc mice received normal chow until 80 and 60 days of age, respectively, then were transferred to either a control diet containing SG (Ctr) or a matched diet lacking SG (−SG) until clinical end point. Serum isolated from terminal bleeds was analysed with a YSI 2950 Biochemistry Analyser for glucose and lactate concentration. Error bars are s.d.

Source data

Extended Data Figure 2 Effect of SG-free diet on serum amino acids.

a, b, ApcMin/+ (a) and Eμ-Myc (b) mice received normal chow until 80 and 60 days of age, respectively, then were transferred to either a control diet containing SG (Ctr) or a matched diet lacking SG (−SG) until clinical end point. Serum isolated from terminal bleeds was analysed by LC–MS. Relative quantity of metabolites are shown (y axis = peak area). Error bars are s.d. P values were calculated for each amino acid by t-test (unpaired, two-tailed), P values <0.05 are shown.

Extended Data Figure 3 SG starvation impedes the growth of established HCT116 tumours by decreasing intratumoural serine and glycine concentration.

a, HCT116 cells were injected bilaterally (3 × 106 per flank, n = 8) and allowed to form tumours. Once tumours were visible and measurable by callipers mice were transferred to control diet or SG-free diet (−SG). Tumours were measured three times per week and average weekly tumour volume is plotted, error bars are s.e.m. P values were calculated by t-test (unpaired, one-tailed). See Source Data. b, HCT116 tumours (taken at clinical end point) were analysed by LC–MS for absolute concentration of SG (1–3 pieces of each tumour were analysed). Data are averages, error bars are s.d. P values were calculated by t-test (unpaired, one-tailed). c, HCT116 cells were grown in vitro (24-well plates) in the intratumoural SG concentrations displayed in b. Medium was replaced every 24 h and cell counts were performed on the stated days. Data are averages of 12 replicate wells for each condition from an individual experiment, error bars are s.d. d, HCT116 cells were grown in vitro (24-well plates, 12 replicate wells for each condition) in the intratumoural SG concentrations displayed in b. Medium was replaced every 24 h and cell counts were performed after four days. Data are averages of three independent experiments, error bars are s.e.m. P values were calculated by t-test (unpaired, one-tailed).

Source data

Extended Data Figure 4 Effect of SG-free diet on ApcMin/+ and Eμ-Myc allograft tumours at temporal end points.

a, Lymphoma cells were isolated from Eμ-Myc mice and allowed to replicate in culture. Cells were injected subcutaneously (5 × 105 per flank) into nude mice and allowed to form tumours. Once tumours (Ctr, n = 4; −SG, n = 4) were visible and measurable, mice were transferred to control (Ctr) or SG-free diet (−SG). Mice were killed and tumours excised at single temporal end point (6 days on diet). Average tumour volume (as percentage of starting tumour volume) is shown, error bars are s.d. See Source Data. b, To assess cell number per subcutaneous Eμ-Myc tumour cross-section, two separate cell counts per tumour (using H&E-stained cross-sections) were performed and averaged, mean of means is shown, error bars are s.e.m. P values calculated by t-test (unpaired, one-tailed). c, Whole subcutaneous Eμ-Myc tumour tissue sections (Ctr, n = 3; −SG, n = 4) were immunostained for cleaved caspase-3 (CC3) and BrdU. Image analysis of non-necrotic regions of whole tumours allowed quantitative evaluation of the percentage of cleaved caspase-3-positive cells per tumour and the percentage of BrdU-positive cells per tumour. Data are averages, error bars are s.d. d, Eμ-Myc tumour (as described in ac above) cross-sections were H&E stained, the scale bar for each image is 4 mm, demonstrative necrotic regions marked with arrows. Additional tumour tissue sections (marked with asterisks) are included for comparison from tumours, which developed after diet change (these three tumours were measurable 2 days post diet change and were present for 4 days on diet before end point). e, Necrosis was quantified by image analysis of necrotic and non-necrotic surface area of H&E stains for the sections shown in d. Error bars are s.d. P value was calculated by t-test (unpaired, one-tailed; Ctr, n = 5; −SG, n = 6). f, ApcMin/+ mice were placed on control diet (Ctr, n = 3) or SG-free diet (−SG, n = 3) at 80 days of age. At a single temporal end point (14 days on diet) mice were killed the small intestine was removed for histological analysis. Tissue sections were immunostained for cleaved caspase-3 and BrdU. Image analysis of whole intestines allowed quantitative evaluation of cell number per adenoma, percentage of CC3-positive cells and percentage of BrdU-positive cells per adenoma. Data are averages of all adenomas identified in each small intestine section, error bars are s.e.m., P values calculated by t-test (unpaired, one-tailed). For all analyses (af), P values below 0.1 are shown.

Source data

Extended Data Figure 5 Metformin treatment did not enhance the anti-tumour effect of SG-free diet in ApcMin/+ mice.

a, To clearly display the effect of metformin on survival of ApcMin/+ mice data from Fig. 2b is re-plotted on two separate graphs; ApcMin/+ mice were transferred to control or SG-free diet (−SG) at 80 days of age, then five days later received Metformin 200 mg kg−1 per day in drinking water. Intestinal-tumour-related survival calculated from change of diet. n, number of mice in cohort; MS, median survival in days. P values calculated by Mantel–Cox test. See Source Data. b, Post-mortem intestinal tumour measurement was performed on intestine tissue. P values calculated by t-test (unpaired, two-tailed). ‘Diet only’ data are replicated from Extended Data Fig. 1a. See Source Data.

Source data

Extended Data Figure 6 Quantification of metformin levels in ApcMin/+ mice.

a, ApcMin/+ mice were transferred to control or SG-free diet (−SG) then received metformin 200 mg kg−1 per day in drinking water. Serum isolated from terminal bleeds was analysed by LC–MS. Error bars are s.d. b, Tissue samples from metformin-treated mice were analysed by LC–MS. NC, normal colon; NSI, normal small intestine; TC, tumour colon; TSI, tumour small intestine. Error bars are s.d. c, For mice where matching serum and tumour (small intestine or colon) tissue samples were available (Ctr diet, n = 7; −SG diet, n = 6), serum versus tumour metformin concentrations are plotted. Metformin concentrations were determined in all samples using a six-point calibration curve using the relevant biological matrix (tissue/serum). d, Serum from ApcMin/+ mice treated with metformin was analysed for glucose and lactate levels using a YSI 2950 Biochemistry Analyser. e, Intestinal tumour organoids derived from a Vil1-creER;Apcfl/fl mouse were grown with or without serine and glycine and with or without daunorubicin at the stated concentrations for two days. Relative change (versus no drug control) in organoid diameter is plotted. Data are average of three independent experiments, error bars are s.e.m. f, Vil1-creER;Apcfl/fl organoids were grown with or without serine and glycine, and with or without daunorubicin for two days, then fixed and stained for malondialdehyde (MDA), data are average of three independent experiments, bars are s.e.m. P values calculated by t-test (unpaired, two-tailed, with correction for multiple comparisons).

Extended Data Figure 7 Effect of SG-free diet on serum amino acids in PDAC mice.

Pdx1-cre;KrasG12D/+;Trp53fl/+ mice received normal chow until 60 days of age, then were transferred to either a control diet containing serine and glycine (Ctr) or a matched diet lacking serine and glycine (−SG) until clinical end point. Serum isolated from terminal bleeds was analysed by LC–MS. Relative quantity of metabolites are shown (y axis = peak area). Error bars are s.d. P values were calculated for each amino acid by t-test (unpaired, two-tailed), P values <0.05 are shown.

Extended Data Figure 8 Effect of SG-free diet on PDAC mice.

a, Pdx1-cre;KrasG12D/+;Trp53R172H/+ mice received control or SG-free (−SG) diet at 60 days of age until clinical end point. PDAC-related survival was calculated from change of diet. P value calculated by Mantel–Cox test. n, number of mice; MS, median survival in days. See Source Data. b, Serum isolated from terminal bleeds of Pdx1-cre;KrasG12D/+;Trp53R172H/+ mice was analysed by LC–MS. Relative quantity of metabolites are shown (y axis = peak area). Error bars are s.d. P values were calculated for each amino acid by t-test (unpaired, two-tailed), P values <0.05 are shown. c, Serum samples from PDAC mice were analysed for glucose and lactate levels using a YSI 2950 Biochemistry Analyser.

Source data

Extended Data Figure 9 Effect of SG-starvation on AMPK phosphorylation, macropinocytosis and SSP protein expression.

a, Tumour-bearing spleens from Eμ-Myc mice and PDAC tissue were analysed by western blot for Ampk and phospho-Ampk levels, bands were quantified by LiCor infrared detection. For gel source data, see Supplementary Fig. 1. Data are averages, error bars are s.d. b, Macropinocytosis in iKras cells was assessed using TMR-labelled dextran uptake assay. Cells were initially grown with or without doxycycline for 48 h then seeded with or without doxycycline and with or without SG for 40 h (final 16 h without FBS), then given TMR dextran/FBS in matched medium for 30 min. Bars and lines show average and s.d. c, Relative changes Kras-ON/Kras-OFF (measured by LiCor infrared quantification) in expression of SSP and phospho-Erk1 protein averaged across iKras1, iKras3 and AK196 cells; the quantified bands are those shown in the western blot of Fig. 3d. Error bars are s.d. d, Protein lysates of tumour-bearing spleens from Eμ-Myc mice and PDAC tissue were analysed for SSP enzyme expression by western blot quantified using a Li-Cor scanner. Relative expression (versus control diet) of SSP enzymes is shown, bars are s.d. Each tissue sample was taken from a different mouse, numbers of mice/tumours are shown above the bars.

Extended Data Figure 10 Effect of SG-free diet on tumour metabolite levels and tumour burden in GEMMs.

a, PDAC from Pdx1-cre;KrasG12D/+;Trp53fl/+ mice and tumour-bearing spleens from Eμ-Myc mice were analysed by LC–MS for serine, glycine, GSH (reduced glutathione) and GSSG (oxidized glutathione). P values calculated by t-test, unpaired, two-tailed. Error bars are s.d. b, S-plot of unbiased metabolomic analysis (OPLS-DA, orthogonal partial least squares discriminant analysis) of Eμ-Myc tumour-bearing spleens (Ctr, n = 20; −SG, n = 13). The detected metabolites showing the greatest decrease due to diet are serine and glycine. Decreased levels of carnitine-related and choline-related metabolites were also observed. Increased levels of phosphatidylcholine (PC) metabolites and alanine and threonine were also seen (as in Extended Data Fig. 2b). SG starvation is known to influence glycolysis and oxidative phosphorylation (potentially explaining changes in carnitine and alanine levels), and one-carbon metabolism (potentially explaining changes in choline-related metabolites). c, Vil1-creER;Apcfl/+;KrasG12D/+ mice were placed on SG-free or control diet at 6–8 weeks of age, then induced with tamoxifen after two weeks and survived until clinical end point (intestinal-tumour-related survival). Post-mortem count of intestinal tumour number and tumour measurement was performed on intestine tissue. Error bars are s.d. P values were calculated by t-test (unpaired, two-tailed). See Source Data.

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Maddocks, O., Athineos, D., Cheung, E. et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544, 372–376 (2017). https://doi.org/10.1038/nature22056

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