Tissue of Origin Dictates GOT1 Dependence and Confers Synthetic Lethality to Radiotherapy

Nelson, Barbara Scott; Lin, Lin; Kremer, Daniel M.; Sousa, Cristovão M.; Cotta‐Ramusino, Cecilia; Myers, Amy L.; Ramos, Johanna; Gao, Ting; Kovalenko, Ilya; Wilder-Romans, Kari; Dresser, Joseph; Davis, Mary A.; Lee, Ho‐Joon; Nwosu, Zeribe C.; Campit, Scott; Mashadova, Oksana; Nicolay, Brandon; Tolstyka, Zachary P.; Halbrook, Christopher J.; Chandrasekaran, Sriram; Asara, John M.; Crawford, Howard C.; Cantley, Lewis C.; Kimmelman, Alec C.; Wahl, Daniel R.; Lyssiotis, Costas A.

doi:10.1101/714196

Cited by 5 publications

(3 citation statements)

References 63 publications

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“…For example, different KRAS mutations likely have tissue-specific effects on metabolism; therefore, multiple strategies must be developed and matched to the mutant RAS subsets. In line with this, there is considerable variation in glutamine dependencies across tissues based on their origin [120][121][122] , and various KRAS mutations can have different dependencies for reasons that are as yet unclear 123 . In vivo, tumors also display variability in their glutamine dependencies when compared to cell culture findings 74 , underscoring the importance of using appropriate model systems to draw firm conclusions.…”

Section: Targeting Oncogenic Ras-related Metabolismmentioning

confidence: 99%

The metabolic landscape of RAS-driven cancers from biology to therapy

2021

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NATuRe CANCeRvarious manners in which oncogenic RAS reprograms metabolism, how these adaptations result in tumor-specific metabolic alterations that in turn modulate oncogenic signaling networks 25,26 and how these metabolic changes may be targeted therapeutically. We focus primarily on KRAS, given the wealth of literature on this major oncogenic driver, and note the roles of other isoforms where these are known.Interplay between oncogenic RAS and glucose metabolism. Altered glucose metabolism, for example, through the Warburg effect, is one of the most common metabolic changes differentiating normal and cancer cells. The breakdown of glucose through glycolysis, in addition to generating ATP, produces metabolic intermediates such as amino acids and precursors for fatty acids and nucleotides that are required for cell growth and proliferation (Fig. 2). Cancer tissueFrequency of mutation (%) Death rate per year Biliary tract 23.3

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Section: Targeting Oncogenic Ras-related Metabolismmentioning

confidence: 99%

The metabolic landscape of RAS-driven cancers from biology to therapy

2021

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“…The cell lines were then cultured in the uridine-supplemented media for 24 h, followed by sample collection as with unlabeled intracellular metabolomics above. Samples for unlabeled and 13 C-(ribose) uridine tracing analyses were run on targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) and processed as previously described (Nelson et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

Nutrient profiling reveals extracellular uridine as a fuel for pancreatic cancer through uridine phosphorylase 1

Ward

Nwosu

Poudel

et al. 2021

Preprint

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Pancreatic ductal adenocarcinoma (PDA) is a lethal disease characterized by high invasiveness, therapeutic resistance, and metabolic aberrations. Although altered metabolism drives PDA growth and survival, the complete spectrum of metabolites used as nutrients by PDA remains largely unknown. Here, we aimed to determine novel nutrients utilized by PDA. We assessed how >175 metabolites impacted metabolic activity in 19 PDA cell lines under nutrient-restricted conditions. This analysis identified uridine as a novel metabolite driver of PDA survival in glucose-deprived conditions. Uridine utilization strongly correlated with expression of the enzyme uridine phosphorylase 1 (UPP1). Metabolomics profiling, notably 13C-stable isotope tracing, revealed that uridine-derived ribose is the relevant component supporting redox balance, survival, and proliferation in glucose-deprived PDA cells. We demonstrate that UPP1 catabolizes uridine, shunting its ribose component into central carbon metabolism to support glycolysis, the tricarboxylic acid (TCA) cycle and nucleotide biosynthesis. Compared to non-tumoral tissues, we show that PDA tumors express high UPP1, which correlated with poor overall survival in multiple patient cohorts. Further, uridine is enriched in the pancreatic tumor microenvironment, and we demonstrate that this may be provided in part by tumor associated macrophages. Finally, we found that inhibition of UPP1 restricted the ability of PDA cells to use uridine, and that UPP1 knockout impairs tumor growth in vivo. Our data identifies uridine catabolism as a critical aspect of compensatory metabolism in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

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“…A recent investigation also showed how tumors that have large antioxidant capacity require an exogenous supply of nonessential amino acids for proliferation (48). Targeting GSH synthesis has been a recurrent therapeutic strategy (41), mainly to sensitize tumor cells in combinatorial therapies (49)(50)(51). That approach has also been tested in IDH1-mutant cancers (36), although in the present work we observed how IDH1-wildtype gliomas were as sensitive as mutant gliomas to cysteine/cystine deprivation and that inhibiting IDH1mutant activity did not affect the response of those cells to this approach.…”

Section: Cysteine/cystine-free Diet Reduces the Levels Of Glutathionementioning

confidence: 99%

Cysteine is a limiting factor for glioma proliferation and survival

Larion

Ruiz‐Rodado

Dowdy

et al. 2021

Preprint

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Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. We report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. 13C-tracing and the analysis of cystathionine synthase and cystathioninase levels revealed the metabolic landscape attributable to cysteine deprivation, and the disconnection between the methionine cycle and the transsulfuration pathway. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, with concomitant reductions in glutathione and cysteine plasma levels. At the end point, however, tumors displayed the ability to synthesize glutathione, although higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine-related metabolites in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

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Tissue of Origin Dictates GOT1 Dependence and Confers Synthetic Lethality to Radiotherapy

Cited by 5 publications

References 63 publications

The metabolic landscape of RAS-driven cancers from biology to therapy

The metabolic landscape of RAS-driven cancers from biology to therapy

Nutrient profiling reveals extracellular uridine as a fuel for pancreatic cancer through uridine phosphorylase 1

Cysteine is a limiting factor for glioma proliferation and survival

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