Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer.

Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor-, progesterone receptor- or human epidermal growth factor 2 receptor-positive (RP) breast cancer. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and may identify new therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. We also identified a lipid metabolism gene signature in patients with TNBC that were identified from The Cancer Genome Atlas database and from multiple other clinical data sets, implicating FAO as a dysregulated pathway that is critical for TNBC cell metabolism. We found that pharmacologic inhibition of FAO catastrophically decreased energy metabolism in MYC-overexpressing TNBC cells and blocked tumor growth in a MYC-driven transgenic TNBC model and in a MYC-overexpressing TNBC patient-derived xenograft. These findings demonstrate that MYC-overexpressing TNBC shows an increased bioenergetic reliance on FAO and identify the inhibition of FAO as a potential therapeutic strategy for this subset of breast cancer

Reprogramming of Glutamate Metabolism and Redox Homeostasis in De Novo MYC-Driven Liver Tumors

Reprogramming of Glutamate Metabolism and Redox Homeostasis in De Novo MYC-Driven Liver TumorsBrittany AndertonMYC overexpressing cells frequently exhibit increased dependence on uptake of glutamine and its conversion to glutamate. However, whether MYC shapes downstream glutamate utilization decisions in vivo is poorly understood. We employed integrated gene expression and metabolite profiling analyses to identify novel metabolic pathways that are altered in primary MYC-driven liver cancers. We identified six metabolic pathways deregulated in MYC-driven liver tumors, including glutathione metabolism. In primary, MYC-driven tumors, glutamine-derived carbons preferentially enter central carbon metabolism and proliferative metabolic pathways and have diminished incorporation into glutathione and its precursor metabolite. We find that protein expression of the rate-limiting enzyme of glutathione synthesis, GCLC, is suppressed in a MYC-dependent manner. We further show that GCLC is targeted by a MYC-induced microRNA, miR-18a. MiR-18a expression is elevated in human hepatocellular carcinoma (HCC) and correlates with altered glutathione pathway gene expression. Further, poorly differentiated human HCCs have low tumor glutathione levels. MYC-driven liver tumors compensate for loss of glutathione by upregulating several antioxidant regeneration pathways. However, MYC-driven liver tumors exhibit increased sensitivity to exogenous oxidative stress, as demonstrated by tumor-specific fat accumulation and cell death following treatment with the potent oxidant diquat. Thus, despite sufficient antioxidant capacity at baseline, MYC-driven liver tumors are sensitive to exogenous oxidative stress. In total, we show that MYC regulates glutamate utilization by attenuating glutathione production via miR-18a, leading to preferential shunting of glutamate toward proliferative metabolism in tumors and altering redox homeostasis mechanisms

Reprogramming of Glutamate Metabolism and Redox Homeostasis in De Novo MYC-Driven Liver Tumors

Reprogramming of Glutamate Metabolism and Redox Homeostasis in De Novo MYC-Driven Liver TumorsBrittany AndertonMYC overexpressing cells frequently exhibit increased dependence on uptake of glutamine and its conversion to glutamate. However, whether MYC shapes downstream glutamate utilization decisions in vivo is poorly understood. We employed integrated gene expression and metabolite profiling analyses to identify novel metabolic pathways that are altered in primary MYC-driven liver cancers. We identified six metabolic pathways deregulated in MYC-driven liver tumors, including glutathione metabolism. In primary, MYC-driven tumors, glutamine-derived carbons preferentially enter central carbon metabolism and proliferative metabolic pathways and have diminished incorporation into glutathione and its precursor metabolite. We find that protein expression of the rate-limiting enzyme of glutathione synthesis, GCLC, is suppressed in a MYC-dependent manner. We further show that GCLC is targeted by a MYC-induced microRNA, miR-18a. MiR-18a expression is elevated in human hepatocellular carcinoma (HCC) and correlates with altered glutathione pathway gene expression. Further, poorly differentiated human HCCs have low tumor glutathione levels. MYC-driven liver tumors compensate for loss of glutathione by upregulating several antioxidant regeneration pathways. However, MYC-driven liver tumors exhibit increased sensitivity to exogenous oxidative stress, as demonstrated by tumor-specific fat accumulation and cell death following treatment with the potent oxidant diquat. Thus, despite sufficient antioxidant capacity at baseline, MYC-driven liver tumors are sensitive to exogenous oxidative stress. In total, we show that MYC regulates glutamate utilization by attenuating glutathione production via miR-18a, leading to preferential shunting of glutamate toward proliferative metabolism in tumors and altering redox homeostasis mechanisms

Semantic Network Analysis Reveals Opposing Online Representations of the Search Term “GMO”

Making sound food and agriculture decisions is important for global society and the environment. Experts tend to view crop genetic engineering, a technology that can improve yields and minimize impacts on the environment, more favorably than the public. Because there is a causal relationship between public opinion and public policy, it is important to understand how opinions about genetically engineered (GE) crops are influenced. The public increasingly seeks science information on the Internet. Here, semantic network analysis is performed to characterize the presentation of the term "GMO (genetically modified organism)," a proxy for food developed from GE crops, on the web. Texts from three sources are analyzed: U.S. federal websites, top pages from a Google search, and online news titles. We found that the framing and sentiment (positive, neutral, or negative attitudes) of "GMO" varies across these sources. It is described how differences in the portrayal of GE food by each source might affect public opinion. A current understanding of the types of information individuals may encounter online can provide insight into public opinion toward GE food. In turn, this knowledge can guide teaching and communication efforts by the scientific community to promote informed decision-making about agricultural biotechnologies

MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer

How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC-driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacylt-RNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC-driven tumors. We find that fewer glutamine-derived carbons are incorporated into GSH in tumor tissue relative to non-tumor tissue. Expression of GCLC, the rate-limiting enzyme of GSH synthesis, is attenuated by the MYC-induced microRNA miR-18a. Inhibition of miR-18a in vivo leads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC-driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC-dependent attenuation of GCLC by miR-18a contributes to GSH depletion in vivo, and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine

MicroRNA‐494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer

UnlabelledHepatocellular carcinoma (HCC) is associated with poor survival for patients and few effective treatment options, raising the need for novel therapeutic strategies. MicroRNAs (miRNAs) play important roles in tumor development and show deregulated patterns of expression in HCC. Because of the liver's unique affinity for small nucleic acids, miRNA-based therapy has been proposed in the treatment of liver disease. Thus, there is an urgent need to identify and characterize aberrantly expressed miRNAs in HCC. In our study, we profiled miRNA expression changes in de novo liver tumors driven by MYC and/or RAS, two canonical oncogenes activated in a majority of human HCCs. We identified an up-regulated miRNA megacluster comprised of 53 miRNAs on mouse chromosome 12qF1 (human homolog 14q32). This miRNA megacluster is up-regulated in all three transgenic liver models and in a subset of human HCCs. An unbiased functional analysis of all miRNAs within this cluster was performed. We found that miR-494 is overexpressed in human HCC and aids in transformation by regulating the G1 /S cell cycle transition through targeting of the Mutated in Colorectal Cancer tumor suppressor. miR-494 inhibition in human HCC cell lines decreases cellular transformation, and anti-miR-494 treatment of primary MYC-driven liver tumor formation significantly diminishes tumor size.ConclusionOur findings identify a new therapeutic target (miR-494) for the treatment of HCC

PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression

Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression

Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer

Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC) compared to estrogen, progesterone and human epidermal growth factor 2 receptor-positive (RP) breast tumors(1,2). We and others have shown that MYC alters metabolism during tumorigenesis(3,4). However, the role of MYC in TNBC metabolism remains largely unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for MYC-overexpressing (MO) TNBC and may thus identify novel therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. A lipid metabolism gene signature was identified in patients with TNBC from The Cancer Genome Atlas (TCGA) database and multiple other clinical datasets, implicating FAO as a dysregulated pathway critical for TNBC metabolism. We find that MO-TNBC displays increased bioenergetic reliance upon fatty acid oxidation (FAO), and that pharmacologic inhibition of FAO catastrophically decreases energy metabolism of MO-TNBC, blocks growth of a MYC-driven transgenic TNBC model and that of MO-TNBC patient-derived xenografts. Our results demonstrate that inhibition of FAO is a novel therapeutic strategy against MO-TNBC