Alteration of the lipid profile in lymphomas induced by MYC overexpression

Eberlin, Lívia S.; Gabay, Meital; Fan, Alice C.; Gouw, Arvin M.; Tibshirani, Robert; Felsher, Dean W.; Zare, Richard N.

doi:10.1073/pnas.1409778111

Cited by 121 publications

(120 citation statements)

References 49 publications

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“…To evaluate whether these pathways have therapeutic value, we performed pharmacological inhibition of glutaminase, which converts glutamine to glutamate for its further oxidation through the TCA cycle. The inhibition of glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) (27) slowed RCC tumor progression, suggesting that targeting the glutaminolytic pathway is a potential therapeutic approach to treat human RCC (24,25).…”

Section: Significancementioning

confidence: 99%

“…We used high-mass resolution and high-mass accuracy desorption electrospray ionization-massspectrometric imaging (DESI-MSI) and molecular biology methods to investigate the changes in metabolites, lipids, proteins, and genes in our RCC model. We used this approach because we previously described the successful use of DESI-MSI and transgenic mouse models to examine the lipid profiles of MYC-induced hepatocellular carcinomas (HCCs) (24) and lymphomas (25).…”

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confidence: 99%

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

Shroff¹,

Eberlin

Dang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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220

217

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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...

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Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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

Shroff¹,

Eberlin

Dang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

220

217

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“…The lipid composition of tumors is also affected by dynamic processes, having been observed to vary with cell proliferation, apoptosis, and necrosis (9). Furthermore, a recent study has revealed distinct lipid signatures in MYC-or RAS-induced lymphoma, suggesting that the observable lipid profile can be related to specific oncogene expression (10). In addition to genotype specificity, evidence suggests that metabolic profiles are highly tissue specific (11).…”

Section: Introductionmentioning

confidence: 99%

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

et al. 2016

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MYC-mediated pathogenesis in lung cancer continues to attract interest for new therapeutic strategies. In this study, we describe a transgenic mouse model of KRAS-driven lung adenocarcinoma that affords reversible activation of MYC, used here as a tool for lipidomic profiling of MYC-dependent lung tumors formed in this model. Advanced mass spectrometric imaging and surface analysis techniques were used to characterize the spatial and temporal changes in lipid composition in lung tissue. We found that normal lung tissue was characterized predominantly by saturated phosphatidylcholines and phosphatidylglycerols, which are major lipid components of pulmonary surfactant. In contrast, tumor tissues displayed an increase in phosphatidylinositols and arachidonate-containing phospholipids that can serve as signaling precursors. Deactivating MYC resulted in a rapid and dramatic decrease in arachidonic acid and its eicosanoid metabolites. In tumors with high levels of MYC, we found an increase in cytosolic phospholipase A2 (cPLA2) activity with a preferential release of membrane-bound arachidonic acid, stimulating the lipoxygenase (LOX) and COX pathways also amplified by MYC at the level of gene expression. Deactivating MYC lowered cPLA2 activity along with COX2 and 5-LOX mRNA levels. Notably, inhibiting the COX/5-LOX pathways in vivo reduced tumor burden in a manner associated with reduced cell proliferation. Taken together, our results show how MYC drives the production of specific eicosanoids critical for lung cancer cell survival and proliferation, with possible implications for the use of COX and LOX pathway inhibitors for lung cancer therapy.

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“…DESI-MSI can rapidly evaluate the tissue metabolome in situ by simultaneously characterizing hundreds of lipids and metabolites. In the last 5 y, reports from our group (16)(17)(18)(19) and others (15,(20)(21)(22) have demonstrated the usefulness of DESI-MSI in viewing the metabolite and lipid distribution in tissue samples from cancers and other diseases. Global changes in metabolism are a cardinal feature of neoplasia (23, 24), and DESI-MSI can determine global metabolite levels and their spatial distributions across a tissue sample on a microscopic slide.…”

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confidence: 99%

Diagnosis of prostate cancer by desorption electrospray ionization mass spectrometric imaging of small metabolites and lipids

Banerjee

Zare

Tibshirani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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186

184

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Accurate identification of prostate cancer in frozen sections at the time of surgery can be challenging, limiting the surgeon's ability to best determine resection margins during prostatectomy. We performed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) on 54 banked human cancerous and normal prostate tissue specimens to investigate the spatial distribution of a wide variety of small metabolites, carbohydrates, and lipids. In contrast to several previous studies, our method included Krebs cycle intermediates (m/z <200), which we found to be highly informative in distinguishing cancer from benign tissue. Malignant prostate cells showed marked metabolic derangements compared with their benign counterparts. Using the "Least absolute shrinkage and selection operator" (Lasso), we analyzed all metabolites from the DESI-MS data and identified parsimonious sets of metabolic profiles for distinguishing between cancer and normal tissue. In an independent set of samples, we could use these models to classify prostate cancer from benign specimens with nearly 90% accuracy per patient. Based on previous work in prostate cancer showing that glucose levels are high while citrate is low, we found that measurement of the glucose/citrate ion signal ratio accurately predicted cancer when this ratio exceeds 1.0 and normal prostate when the ratio is less than 0.5. After brief tissue preparation, the glucose/citrate ratio can be recorded on a tissue sample in 1 min or less, which is in sharp contrast to the 20 min or more required by histopathological examination of frozen tissue specimens.prostate cancer | Krebs cycle | metabolism | desorption electrospray ionization | mass spectrometry P rostate cancer (PCa) is the most commonly diagnosed solidorgan cancer and the second leading cause of cancer death in men in the United States (1). Because of prostate-specific antigen (PSA) screening in the United States, most PCas are discovered when they are confined to the prostate (2). Many of these localized PCas are treated by surgical removal of the entire prostate (radical prostatectomy). The presence of cancer cells at the edge of the surgical resection, or positive surgical margins, is associated with higher rates of recurrence and death from PCa (3, 4). Therefore, an important clinical challenge in PCa management is to devise a rapid and highly accurate method to detect cancerous cells in real time to allow resection of additional periprostatic tissues and reduce cancer recurrence after surgery. Over the last decade, several innovative analytical techniques (5-12) have been developed to distinguish cancer from benign tissue in various organs. However, none has achieved wide clinical adoption for various reasons including inconvenience, narrow information content, unavailability, poor sensitivity, slowness of adoption, and operating room workflow incompatibility. In PCa, intraoperative frozen sections have been used to attempt to identify PCa at the margin based on analysis of histology. However, frozen sections h...

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Alteration of the lipid profile in lymphomas induced by MYC overexpression

Cited by 121 publications

References 49 publications

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

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

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

Diagnosis of prostate cancer by desorption electrospray ionization mass spectrometric imaging of small metabolites and lipids

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