MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Abstract

The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.MYC oncogene | renal cell carcinoma | desorption electrospray ionization mass spectrometry imaging | glutamine metabolism R enal cell adenocarcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport waste molecules from the blood to the urine. Most patients who present with advanced RCC have a dismal prognosis because RCC easily metastasizes and advances in therapy have been limited (1-3). A lack of transgenic models of RCC has made it difficult to identify and test new therapeutic modalities.The MYC pathway is activated in most cases of human RCC (4), genomically amplified in 5-10% of patients, overexpressed in 20% (5), and associated with a hereditary RCC syndrome (6) suggesting a causal role in the pathogenesis, but this has never been examined. Here, we report the development of a conditional transgenic mouse model for MYC-deregulated human RCC. The MYC oncogene contributes to tumorigenesis of many types of cancer through various mechanisms (7-10), including the regulation of proliferation and growth, protein and ribosomal biogenesis, changes in metabolism, lipid synthesis, and induction of angiogenesis (11)(12)(13)(14). MYC reprogramming can result in tumors that are addicted to glucose and/or glutamine for their energy metabolism (15-19). MYC directly regulates specific genes of the glycolytic and glutaminolytic pathways (15,17,20,21), including lactate dehydrogenase A (LDHA), glucose transporter 1 (Glut1), hexokinase 2 (HK2), phosphofructokinase-M 1 (PFKM1), and enolase 1 (Eno1) (21-23). Also, MYC coordinates genes involved in glutamine catabolism (SI MYC and Glutamine Catabolism). However, there has been no evidence to show that MYC overexpression directly drives and maintains RCC or how this occurs.Through our new transgenic mouse model, we showed that transgenic MYC, but not mutant RAS, overexpression in vivo rapidly initiates a highly aggressive RCC that histologi...

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

“…The Cancer Genome Atlas (TCGA) pan-cancer gene expression data show high expression of GLS in acute myeloid leukemia, adrenocortical cancer, triple-negative breast cancer, colorectal cancer, kidney clear or papillary cell carcinoma, lung adenocarcinoma, melanoma, mesothelioma, pancreatic cancer, sarcoma and thyroid cancer [78,79]. Of these, GLS activity has been shown to be important for growth of acute myeloid leukemia [80][81][82], breast cancer [61,64,83,84], colorectal cancer [85], kidney cancer [86,87], lung cancer [88], melanoma [89,90] and pancreatic cancer cells [91] in studies that utilized smallmolecule inhibitors or gene-silencing approaches in cell lines. Further, glioblastoma cell lines have been found to be sensitive to glutaminase inhibitors in vitro, despite having relatively low GLS expression according to TCGA data [80,92].…”

Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways

“…PI3P and phosphatidylserine (C16) liposomes were generated by sonication in 2× lipid mixture buffer (40 mM Tris-HCl, pH 7.4, 200 mM NaCl, 1 mM EGTA), with or without FTY720. FLAG-PIKfyve and lipid mixtures were incubated with Mg Measurement of PI (3,5)P 2 by HPLC. HeLa cells were rinsed twice with PBS and incubated for 48 hours in inositol labeling medium (inositol-free DMEM containing 5 μg/ml transferrin, 5 μg/ml insulin, 10% dialyzed FCS, 20 mM HEPES, 2 mM L-glutamine) and 10 μCi/ml myo-[2-3 H]-inositol.…”

“…To meet the anabolic demands of cell division, oncogenic mutations drive glucose and glutamine transporter gene expression (1)(2)(3)(4). The LDL receptor is similarly upregulated in cancer cells to provide exogenous cholesterol and fatty acids that fuel cell growth (5,6).…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Nevertheless, glutamine metabolism has been documented as critical for tumorigenesis and tumor survival in specific in vivo models 151,173,192,193 , which have varied metabolic profiles depending on the tumor oncogenotype. The complexities in vivo are exemplified by a study utilizing mouse models to compare the effects of metabolic driver and tissue of origin on tumor metabolism 177 ( Figure 8).…”