Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer

Achreja, Abhinav; Yu, Tao; Mittal, Anjali; Choppara, Srinadh; Animasahun, Olamide; Nenwani, Minal; Wuchu, Fulei; Meurs, Noah; Mohan, Avvari V.; Jeon, Jin Heon; Sarangi, Itisam; Jayaraman, Anusha; Owen, Sarah; Kulkarni, Reva; Dziubinski, Michele L.; Weinberg, Frank; Kweon, Hye Kyong; Subramanian, Chitra; Wicha, Max S.; Merajver, Sofía D.; Nagrath, Sunitha; Cho, Kathleen R.; DiFeo, Analisa; Lu, Xiongbin; Nagrath, Deepak

doi:10.1038/s42255-022-00636-3

Cited by 23 publications

(13 citation statements)

References 86 publications

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“…The 13 C-MFA models we develop in this work provide insights into metabolic rewiring that are difficult to glean with simpler analysis techniques 34,35,[45][46][47] . While de novo synthesis of both purines and pyrimidines is elevated in GBM compared to cortex, salvage of uridine and hypoxanthine appears to dominate nucleotide production.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a nucleotide formed only from infused 13 C-containing sources at a low rate might have higher 13 C enrichment than a nucleotide formed from unlabeled sources at a faster rate. Therefore, we developed a metabolic flux analysis (MFA) approach to directly quantify nucleotide synthesis fluxes from in vivo enrichment data (Fig 4A) 34 . We then applied this mathematical framework to our patient-derived orthotopic GBM mouse models to determine if higher GBM nucleotide enrichment corresponds to higher synthetic flux.…”

Section: Gliomas Increase Flux Of Nucleotide Synthesis and Decrease O...mentioning

confidence: 99%

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Rewiring of cortical glucose metabolism fuels human brain cancer growth

Scott,

Mittal,

Meghdadi

et al. 2023

Preprint

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The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth.

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Section: Discussionmentioning

confidence: 99%

Section: Gliomas Increase Flux Of Nucleotide Synthesis and Decrease O...mentioning

confidence: 99%

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Scott,

Mittal,

Meghdadi

et al. 2023

Preprint

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“…While this study directly explored SLC25A51 in AML cells, our findings provide a rationale for more broadly exploring its roles in other tumor types that depend on oxidative mitochondrial metabolism. A recent study identified that an oxidative mitochondrial NAD + /NADH ratio was critical in ovarian cancer (42), and another reported that high SLC25A51 levels in hepatocellular carcinoma (HCC) promoted cancer progression through SIRT5 activation (43). Additionally, there are some phenotypic similarities between SLC25A51 loss in AML and block of mitochondrial pyruvate carrier in oxidative Non-Hodgkin Diffuse Large B Cell Lymphomas (44).…”

Section: Discussionmentioning

confidence: 99%

SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux

Busquets

Impedovo

et al. 2022

Preprint

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SLC25A51 imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining oxidative metabolism in human mitochondria. We observed that higher expression of SLC25A51 correlated with poorer survival in Acute Myeloid Leukemia (AML) patient data. Given AML's dependency on oxidative cell metabolism, we sought to determine the role SLC25A51 may serve in this disease. We found that depleting SLC25A51 in AML cells led to increased apoptosis, as well as prolonged survival in a xenograft model. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from oxidative pathways and promoted glutamine utilization for reductive carboxylation to support aspartate production. Consequently, SLC25A51 loss sensitized AML cells to glutamine deprivation and glutaminase inhibitor CB-839. Together, the work highlights connections between SLC25A51 and oxidative mitochondrial flux in AML. We identified a rationale for targeting SLC25A51 in myeloid cancers with potential for a therapeutic window, especially when coupled with glutaminase inhibition.

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“…For example, isotopologues with multiple labels have been used to quantitate mass spectrometry measurements, to uncover regulation of flux, and to obtain enzymatic rates. − By measuring specifically labeled NAD pools amid complex mixtures, researchers can quantitatively determine alterations in flux and concentrations. In the example of the mammalian mitochondrial NAD + transporter, − kinetic rate measurements of NAD + uptake in intact and respiring mitochondria were made feasible with radiolabeled NAD + , and investigation into the roles of mitochondrial NAD + in cells was feasible with heavy-atom labeled NAD + . − Labeled NAD + molecules were distinguishable from the unlabeled resident pool, allowing small additions to be measured over the course of the experiments; this resolution could not have been achieved by simply measuring final mitochondrial NAD + amounts. Moreover, specific advantages of isotopologues include that they are structurally identical and recognized by endogenous enzymes as cognate substrates.…”

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confidence: 99%

Improved Yield for the Enzymatic Synthesis of Radiolabeled Nicotinamide Adenine Dinucleotide

Eller

Goyal

Cambronne

2023

ACS Bio Med Chem Au

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Labeled β-nicotinamide adenine dinucleotide (NAD) analogues have been critical for uncovering new biochemical connections and quantitating enzymatic activity. They function as tracers for enzymology, flux analyses, and in situ measurements. Nevertheless, there is limited availability of specific types of analogues, especially radiolabeled NAD isotopologues. Here, we describe an improved enzymatic synthesis reaction for 32 P-NAD + with a yield of 98% ± 1%, using lowered concentrations of reactants and standard equipment. This represents the highest reported yield for the enzymatic synthesis of NAD + to date. With the high yield we were able to directly use the reaction product to generate derivatives, such as 32 P-NADP. The high-yield enzymatic synthesis is versatile for a broad variety of labels and NAD derivatives. Its advantages include lowered concentrations of reactants, providing sufficient amounts of product for downstream applications, and minimizing intermediate purification steps.

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Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer

Cited by 23 publications

References 86 publications

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Rewiring of cortical glucose metabolism fuels human brain cancer growth

SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux

Improved Yield for the Enzymatic Synthesis of Radiolabeled Nicotinamide Adenine Dinucleotide

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