Biology subjects

Luengo, A.

Publications and source records attributed to Luengo, A..

3 recordsLinked to original sources

bioRxiv2020

Increased demand for NAD+ relative to ATP drives aerobic glycolysis

Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is a hallmark of proliferative metabolism that is observed across many organisms and conditions. To better understand why aerobic glycolysis is associated with cell proliferation, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase mitochondrial pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the nicotinamide adenine dinucleotide cofactor ratio (NAD+/NADH). This change in NAD+/NADH ratio is caused by an increase in mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling mitochondrial respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when the demand for NAD+ to support oxidation reactions exceeds the demand for ATP consumption in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation despite available oxygen. This argues that cells engage in aerobic glycolysis when the cellular demand for NAD+ is in excess of the cellular demand for ATP.

biochemistry↗

bioRxiv2020

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

A hallmark of metastasis is the adaptation of tumor cells to new environments. Although it is well established that the metabolic milieu of the brain is severely deprived of nutrients, particularly the amino acids serine and its catabolite glycine, how brain metastases rewire their metabolism to survive in the nutrient-limited environment of the brain is poorly understood. Here we demonstrate that cell-intrinsic de novo serine synthesis is a major determinant of brain metastasis. Whole proteome comparison of triple-negative breast cancer (TNBC) cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis and improved overall survival in mice, whereas expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Collectively, these findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain. Statement of SignificanceOur study highlights how limited serine and glycine availability within the brain microenvironment potentiates tumor cell sensitivity to serine synthesis inhibition. This finding underscores the importance of studying cancer metabolism in physiologically-relevant contexts, and provides a rationale for using PHGDH inhibitors to treat brain metastasis.

cancer biology↗

bioRxiv2019

Pancreatic Stellate Cells Secrete Deoxycytidine Conferring Resistance to Gemcitabine in PDAC

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the United States. The deoxynucleoside analog gemcitabine is among the most effective therapies to treat PDAC; however, nearly all patients treated with gemcitabine either fail to respond or rapidly develop resistance. One hallmark of PDAC is a striking accumulation of stromal tissue surrounding the tumor, and this accumulation of stroma can contribute to therapy resistance. To better understand how stroma limits response to therapy, we investigated cell-extrinsic mechanisms of resistance to gemcitabine. We show that conditioned media from pancreatic stellate cells (PSC), as well as from other fibroblasts, protects PDAC cells from gemcitabine toxicity. We find that the PSC conditioned media protective effect is mediated by secretion of deoxycytidine, but not other deoxynucleosides, through equilibrative nucleoside transporters. Deoxycytidine inhibits the processing of gemcitabine in PDAC cells, thus reducing the effect of gemcitabine and other nucleoside analogs on cancer cells. Our results suggest that reducing deoxycytidine production in PSCs may increase the efficacy of nucleoside analog therapies. Additional InformationFunding: This project was funded in part by the NIH (NCI U54-217377), the MIT Center for Precision Cancer Medicine, and by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute. S.D. was supported by the David H. Koch Fellowship in Cancer Research. A.N.L was a Robert Black Fellow of the Damon Runyon Cancer Research Foundation, DRG-2241-15 and was supported by a NIH Pathway to Independence Award (K99/R00), 1K99CA234221. M.T.H and M.G.V.H. acknowledges funding from the MIT Center for Precision Cancer Medicine and the Ludwig Center at MIT. M.G.V.H also acknowledges funding from the Lustgarten Foundation, SU2C, the MIT Center for Precision Cancer Medicine, the NCI, and an HHMI Faculty Scholar award. Competing interests: M.G.V.H. is a consultant and advisory board member for Agios Pharmaceuticals, Aeglea Biotherapeutics, and Auron Therapeutics.

cancer biology↗