title: Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis.
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.
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden. jonas.a.nilsson@surgery.gu.se
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Nilsson
authors.forename: Tacha Zi Plym
authors.initials: TZ
authors.lastname: Forshell
authors.forename: Sara
authors.initials: S
authors.lastname: Rimpi
authors.forename: Christiane
authors.initials: C
authors.lastname: Kreutzer
authors.forename: Walter
authors.initials: W
authors.lastname: Pretsch
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D007527:Isoenzymes; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D050543:Phosphoglycerate Dehydrogenase; D012696:Glycine Hydroxymethyltransferase; C559685:Shmt1 protein, mouse