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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Adenomatous Polyposis Coli Protein

genetics

Animals

Cell Transformation

Neoplastic

Disease Models

Animal

Fibroblasts

Gene Expression Regulation

Neoplastic

Genes

ras

genetics

Glycine Hydroxymethyltransferase

genetics

metabolism

Humans

Isoenzymes

genetics

metabolism

L-Lactate Dehydrogenase

genetics

metabolism

Lymphoma

B-Cell

genetics

metabolism

Metabolic Networks and Pathways

Mice

Mice

Inbred C57BL

Mice

Transgenic

NIH 3T3 Cells

Oligonucleotide Array Sequence Analysis

Phosphoglycerate Dehydrogenase

genetics

metabolism

Proto-Oncogene Proteins c-myc

genetics

metabolism

Tumor Suppressor Protein p53

genetics

Tumour biology

biology

genetik

Publikations- och innehållstyp

ref (ämneskategori)

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