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.2012;8(3):e1002573.
doi: 10.1371/journal.pgen.1002573. Epub 2012 Mar 15.

Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis

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Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis

Lisa M Nilsson et al. PLoS Genet.2012.

Abstract

c-Myc (hereafter called Myc) belongs to a family of transcription factors that regulates cell growth, cell proliferation, and differentiation. Myc initiates the transcription of a large cast of genes involved in cell growth by stimulating metabolism and protein synthesis. Some of these, like those involved in glycolysis, may be part of the Warburg effect, which is defined as increased glucose uptake and lactate production in the presence of adequate oxygen supply. In this study, we have taken a mouse-genetics approach to challenge the role of select Myc-regulated metabolic enzymes in tumorigenesis in vivo. By breeding λ-Myc transgenic mice, Apc(Min) mice, and p53 knockout mice with mouse models carrying inactivating alleles of Lactate dehydrogenase A (Ldha), 3-Phosphoglycerate dehydrogenase (Phgdh) and Serine hydroxymethyltransferase 1 (Shmt1), we obtained offspring that were monitored for tumor development. Very surprisingly, we found that these genes are dispensable for tumorigenesis in these genetic settings. However, experiments in fibroblasts and colon carcinoma cells expressing oncogenic Ras show that these cells are sensitive to Ldha knockdown. Our genetic models reveal cell context dependency and a remarkable ability of tumor cells to adapt to alterations in critical metabolic pathways. Thus, to achieve clinical success, it will be of importance to correctly stratify patients and to find synthetic lethal combinations of inhibitors targeting metabolic enzymes.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Myc regulates the metabolic transcriptome.
(A) Unsupervised hierarchical clustering of Illumina bead arrays made from RNA of splenic B cells from three wildtype and four precancerous λ-Myc transgenic mice. See Table S1 for genes used in the clustering. (B) qRT-PCR confirmation of 4 of the 20 most significantly, or most elevated expressed genes, in B220-sorted B cells from λ-Myc transgenic mice. *indicates p<0.05 and ** indicates p<0.01.
Figure 2
Figure 2.Shmt1 loss accelerates lymphomagenesis in λ-Myc transgenic mice.
(A) Survival curve of λ-Myc mice generated from interbreedings betweenShmt1 knockout and λ-Myc transgenic mice. λ-Myc;Shmt1+/+ n = 19, λ-Myc;Shmt1+/− n = 18, λ-Myc;Shmt1−/− n = 20. (B) Survival curve ofp53 knockout mice of the indicatedShmt1 genotypes.p53−/−;Shmt1+/+ n = 22,p53−/−;Shmt1−/− n = 21. (C) Amount of adenomas inApcMin mice with differentShmt1 genotypes.
Figure 3
Figure 3. Phgdh is dispensable for lymphomagenesis in λ-Myc transgenic mice.
(A) Survival curve of λ-Myc mice generated from interbreedings betweenPhgdh+/− and λ-Myc transgenic mice. λ-Myc;Phgdh+/+ n = 21, λ-Myc;Phgdh+/− n = 23. (B) Amount of adenomas inApcMin mice with differentPhgdh genotypes. (C) Enzymatic activity of Phgdh analyzed in six λ-Myc;Phgdh+/+ and in six λ-Myc;Phgdh+/− lymphomas. (D) Western blot analysis confirming that Phgdh is absent in tumors arising in recipient mice from λ-Myc;Phgdh−/− embryos. (E) Survival curve of C57BL/6 mice transplanted with l-Myc transgenic E13.5 FLC of indicatedPhgdh genotype. λ-Myc;Phgdh+/+ n = 5, λ-Myc;Phgdh+/− n = 14, λ-Myc;Phgdh−/− n = 7.
Figure 4
Figure 4.Ldha is dispensable for Myc-induced lymphomagenesis but not for the development of Ras-induced fibrosarcomas.
(A) Survival curve of λ-Myc mice generated from interbreedings betweenLdhamut/mut and l-Myc transgenic mice. λ-Myc;Ldha+/+ n = 13, λ-Myc;Ldha+/mut n = 26, λ-Myc;Ldhamut/mut n = 21. The p-value is derived from comparing the survival of λ-Myc;Ldha+/+ to λ-Myc;Ldhamut/mut mice. (B) Survival curve of λ-Myc mice generated from interbreedings betweenLdhamut/mut,p53 knockout and λ-Myc transgenic mice. λ-Myc;p53+/−;Ldha+/+ n = 19, λ-Myc;p53+/−;Ldha+/mut n = 9, λ-Myc;p53+/−;Ldhamut/mut n = 17. The p-value is derived from comparing the survival of λ-Myc;p53+/−;Ldha+/+ to λ-Myc;p53+/;Ldhamut/mut mice. (C) Amount of adenomas inApcMin mice with differentLdha genotypes. (D) MEFs of differentLdha genotypes were infected with oncogenic Ras. After subcutaneous injection into syngenic C57BL/6 mice, tumor weights were monitored 16 days post-injection. Two mice were injected with cells perLdha genotype and the experiment was repeated with three different MEF isolates perLdha genotype.
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