Mouse Genetics Suggests Cell-Context Dependency for Myc-Regulated Metabolic Enzymes during Tumorigenesis
2012 (English)In: PLOS Genetics, ISSN 1553-7390, Vol. 8, no 3, e1002573- p.Article in journal (Refereed) Published
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-Myctransgenic mice, ApcMin 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.
Place, publisher, year, edition, pages
2012. Vol. 8, no 3, e1002573- p.
Cell and Molecular Biology
Research subject biology; Genetics
IdentifiersURN: urn:nbn:se:umu:diva-46562DOI: 10.1371/journal.pgen.1002573ISI: 000302254800048OAI: oai:DiVA.org:umu-46562DiVA: diva2:438875
Manuscript version included in thesis had the title "Mouse genetics suggest that metabolic enzymes dispensable for Myc-induced lymphomagenesis can play critical roles for Ras-induced fibrosarcoma growth"2011-09-052011-09-052012-05-30Bibliographically approved