Biology subjects

Nelson, B. S.

Publications and source records attributed to Nelson, B. S..

6 recordsLinked to original sources

bioRxiv2023

Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia

Activating mutations in KRAS extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS. The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of KrasG12D-driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant G6pd accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.

cancer biology↗

bioRxiv2020

The Pancreatic Tumor Microenvironment Buffers Redox Imbalance Imposed by Disrupted Mitochondrial Metabolism

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) restricts vascularization and, consequently, access to blood-derived nutrients and oxygen, which impacts tumor growth. Intracellular redox imbalance is another restraint on cellular proliferation, yet it is unknown if the TME contributes to the maintenance of redox homeostasis in PDA cells. Here, we demonstrate that the loss of mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2), a component in the malate-aspartate shuttle, disturbs redox homeostasis and halts proliferation of PDA cells in vitro. In contrast, GOT2 inhibition has no effect on in vivo tumor growth or tumorigenesis in an autochthonous model. We propose that this discrepancy is explained by heterocellular pyruvate exchange from the TME, including from cancer associated fibroblasts. More broadly, pyruvate similarly confers resistance to inhibitors of mitochondrial respiration. Genetic or pharmacologic inhibition of pyruvate uptake or metabolism abrogated pyruvate-mediated alleviation of reductive stress from NADH buildup. In sum, this work describes a potential resistance mechanism mediated by metabolic crosstalk within the pancreatic TME. These findings have important implications for metabolic treatment strategies since several mitochondrial inhibitors are currently in clinical trials for PDA and other cancers.

cancer biology↗

bioRxiv2020

Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by a heterogenous and densely fibrotic microenvironment. This limits functional vasculature and diffusion of nutrients through the tumor1,2. Accordingly, pancreatic cancer cells develop numerous metabolic adaptations to survive and proliferate in nutrient austere conditions3-7. Subtypes of PDA have been characterized by transcriptional and functional differences8-12, which have been reported to exist within the same tumor13-15. However, it remains unclear if this diversity extends to metabolic programming. Here, using a combination of metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses within neoplastic populations isolated from a single pancreatic tumor. Furthermore, these populations are poised for metabolic crosstalk, and in examining this, we find an unexpected role for asparagine in maintaining cell proliferation following mitochondrial inhibition. Functionally, when challenged by mitochondrial inhibition, asparagine supplementation increases intracellular levels of asparagine and aspartate, a rate limiting biosynthetic precursor16-18. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes pancreatic tumors to mitochondrial targeting with phenformin. Together, these data extend the concept of metabolic diversity to neoplastic populations within individual tumors, while illustrating a new method of intratumoral communication that supports tumor fitness19,20. Finally, the combination of asparaginase with mitochondrial inhibition could provide a powerful new strategy for this difficult to treat disease.

cancer biology↗

bioRxiv2020

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance, and new strategies that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we found that purine metabolites strongly correlated with radiation resistance. Inhibiting purine, but not pyrimidine, synthesis radiosensitized GBM cells and patient-derived neurospheres by impairing DNA repair in a nucleoside-dependent fashion. Likewise, administration of exogenous purine nucleosides protected sensitive GBM models from radiation by promoting DNA repair. Combining an FDA-approved inhibitor of de novo purine synthesis with radiation arrested growth in GBM xenograft models and depleted intratumoral guanylates. High expression of the rate-limiting enzyme of de novo GTP synthesis was associated with shorter survival in GBM patients. Together, these findings indicate that inhibiting de novo purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.

neuroscience↗

bioRxiv2020

GOT1 Inhibition Primes Pancreatic Cancer for Ferroptosis through the Autophagic Release of Labile Iron

Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest solid malignancies, with a 5-year survival rate at ten percent. PDA have unique metabolic adaptations in response to cell-intrinsic and environmental stressors, and identifying new strategies to target these adaptions is an area of active research. We previously described a dependency on a cytosolic aspartate aminotransaminase (GOT1)-dependent pathway for NADPH generation. Here, we sought to identify metabolic dependencies induced by GOT1 inhibition that could be exploited to selectively kill PDA. Using pharmacological methods, we identified cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. Targeting any of these pathways was synthetic lethal in GOT1 knockdown cells and triggered ferroptosis, an oxidative, non-apoptotic, iron-dependent form of cell death. Mechanistically, GOT1 inhibition promoted the activation of autophagy in response to metabolic stress. This enhanced the availability of labile iron through ferritinophagy, the autolysosome-mediated degradation of ferritin. In sum, our study identifies a novel biochemical connection between GOT1, iron regulation, and ferroptosis, and suggests the rewired malate-aspartate shuttle plays a role in protecting PDA from severe oxidative challenge. HighlightsO_LIPDA exhibit varying dependence on GOT1 for in vitro and in vivo growth. C_LIO_LIExogenous cystine, glutathione synthesis, and lipid antioxidant fidelity are essential under GOT1 suppression. C_LIO_LIGOT1 inhibition sensitizes pancreatic cancer cell lines to ferroptosis. C_LIO_LIGOT1 inhibition represses anabolic metabolism and promotes the release of iron through autophagy. C_LI

cancer biology↗

bioRxiv2019

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

Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. Here we tested if tissue type impacted GOT1 dependence by comparing PDA and colorectal cancer (CRC) cell lines and tumor models of similar genotype. We found CRC to be insensitive to GOT1 inhibition, contrasting markedly with PDA, which exhibit profound growth inhibition upon GOT1 knockdown. Utilizing a combination of metabolomics strategies and computational modeling, we found that GOT1 inhibition disrupted glycolysis, nucleotide metabolism, and redox homeostasis in PDA but not CRC. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Taken together, these results illustrate the role of tissue type in dictating metabolic dependencies and provide new insights for targeting metabolism to treat PDA.

cancer biology↗