Biology subjects

Deik, A.

Publications and source records attributed to Deik, A..

9 recordsLinked to original sources

bioRxiv2025

Intraoperative arteriovenous patient sampling to assess in situ non-small cell lung cancer metabolism

We performed intraoperative arteriovenous sampling in participants undergoing surgical resection for non-small cell lung cancer (NSCLC) to characterize in situ tumor metabolism, directly measuring metabolite consumption and secretion in tumor-bearing lung versus normal lung and the systemic circulation. Healthy lung tissue secreted lower levels of lactate, pyruvate, and tricarboxylic acid (TCA) intermediates and consumed less glucose compared to the systemic circulation. In contrast, tumor-bearing lung demonstrated elevated lactate secretion, along with increased efflux of succinate, fumarate, glycine, and aspartate, despite similar glucose uptake. Lactate secretion correlated with tumor PET avidity but not size, and overall metabolic profiles distinguished cancerous from normal lung tissue. These findings confirm enhanced glycolysis in NSCLC in vivo, while also revealing context-dependent patterns of TCA metabolite accumulation and amino acid secretion. Our results demonstrate the utility of intraoperative sampling to uncover metabolic features of human tumors.

cancer biology↗

bioRxiv2025

Abnormal Lipid Metabolism and Altered Neuronal Support by Astrocytes Lacking Akap11, a Risk Gene for Schizophrenia and Bipolar Disorder

A-Kinase Anchoring Protein 11 (AKAP11) is a shared genetic risk factor for schizophrenia and bipolar disorder, yet its role in the brain remains poorly understood. Through multi-omic analysis of Akap11 mutant mouse brains and cultured astrocytes, we identified significant transcriptomic, proteomic, and metabolomic alterations. Key findings include the upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid species such as cholesteryl esters, triacylglycerols, ceramides, and glycerophospholipids, and elevated levels of 3,5-cyclic AMP and protein kinase A (PKA) signaling. These metabolic perturbations manifested as increased lipid droplet accumulation in Akap11 mutant astrocytes, highlighting AKAP11s critical role in regulating intracellular lipid homeostasis. Mechanistically, AKAP11 functions as an autophagy receptor mediating PKA degradation and interacts with endoplasmic reticulum-resident proteins VAP-A and VAP-B through its FFAT motif, providing possible molecular insight into AKAP11s regulation of lipid metabolism. Co-culture experiments with mouse astrocytes and human induced pluripotent stem cell-derived neurons demonstrated that loss of Akap11 in astrocytes, relative to wild-type, increases excitatory neurotransmission and neuronal activity. Collectively, these findings link AKAP11-mediated lipid and synaptic dysregulation to psychiatric disease risk and highlight the potential role of astrocytes in these disorders.

cell biology↗

bioRxiv2025

Epigenetic changes, neuronal dysregulation and metabolomic abnormalities in Zmym2 mutant mice, a genetic model of schizophrenia and neurodevelopmental disorders

Loss-of-function mutations in ZMYM2 are associated with an increased risk of schizophrenia (SCZ) and neurodevelopmental disorders (NDD). ZMYM2 interacts with proteins involved in histone modification and gene regulation, including LSD1 and ADNP; however, its specific roles in the brain remain poorly understood. In this multi-omics study, we demonstrate that heterozygous knockout of Zmym2 in mice results in widespread disturbances in gene expression affecting diverse molecular pathways, including those related to histone modifications and neuronal activity. Proteomic analysis of synapses reveals dysregulation of lipid metabolism and neurofilament-associated pathways, while metabolomic profiling identifies alterations in sphingomyelin and ceramide levels. Furthermore, Zmym2 mutant mice exhibit abnormal brain oscillation patterns on EEG and locomotor hyperactivity in the open field test. Collectively, these findings underscore the critical role of ZMYM2 in brain development and function and highlight Zmym2 mutant mice as a genetic animal model for SCZ and NDD.

neuroscience↗

bioRxiv2024

ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states

AbstractAngiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.

cell biology↗

bioRxiv2023

Vaginal Lactobacillus fatty acid response mechanisms reveal a novel strategy for bacterial vaginosis treatment

Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related species, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). FarE mediates OA resistance, while OhyA is robustly active in the human vaginal microbiota and sequesters OA in a derivative form that only ohyA-harboring organisms can exploit. Finally, OA promotes L. crispatus dominance more effectively than antibiotics in an in vitro model of BV, suggesting a novel approach for treatment.

microbiology↗

bioRxiv2023

Screening in serum-derived medium reveals differential response to compounds targeting metabolism

INTRODUCTION INTRODUCTION RESULTS DISCUSSION KEY RESOURCES TABLE CONTACT FOR REAGENT AND... EXPERIMENTAL MODEL AND SUBJECT... METHOD DETAILS QUANTIFICATION AND STATISTICAL... Data resources DATA AND SOFTWARE AVAILABILITY AUTHOR CONTRIBUTIONS DECLARATION OF INTERESTS REFERENCES Studies of cancer cells in standard culture conditions have long been used as a tractable tool for drug discovery. Cell culture provides unparalleled experimental flexibility, scalability, and low cost to identify and understand the response to cancer therapeutics; however, drug responses in culture are not always predictive of drug response in animal models or in patients1 ...

cancer biology↗

bioRxiv2019

EDEM3 modulates plasma triglyceride level through its regulation of LRP1 expression

Human genetics studies have uncovered genetic variants that can be used to guide biological research and prioritize molecular targets for therapeutic intervention for complex diseases and metabolic conditions. We have identified a missense variant (P746S) in EDEM3 associated with lower blood triglyceride (TG) levels in >300,000 individuals. Functional analyses in cell and mouse models show that EDEM3 deficiency strongly increased the uptake of very low-density lipoprotein and thereby reduced the plasma TG level, as a result of up-regulated expression of LRP1 receptor. We demonstrate that EDEM3 deletion up-regulated the pathways for RNA and ER protein processing and transport, and consequently increased the cell surface mannose-containing glycoproteins, including LRP1. Metabolomics analyses reveal a cellular TG accumulation under EDEM3 deficiency, a profile consistent with individuals with carrying EDEM3 P746S. Our study identifies EDEM3 as a regulator of blood TG, and targeted inhibition of EDEM3 may provide a complementary approach for lowering elevated blood TG concentrations.

genetics↗

bioRxiv2019

A prospective analysis of circulating plasma metabolomics and ovarian cancer risk

We assessed the association of pre-diagnostic plasma metabolites (N=420) with ovarian cancer risk. We included 252 cases and 252 matched controls from the Nurses Health Studies. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) comparing the 90th-10th percentile in metabolite levels, using permutation tests to account for testing multiple correlated hypotheses. Weighted gene co-expression network analysis (WGCNA) modules (n=10) and metabolite set enrichment analysis (MSEA; n=23) were also evaluated. Pseudouridine had the strongest statistical association with ovarian cancer risk overall (OR=2.56, 95%CI=1.48-4.45; p=0.001/adjusted-p=0.15). C36:2 phosphatidylcholine (PC) plasmalogen had the strongest statistical association with lower risk (OR=0.11, 95%CI=0.03-0.35; p<0.001/adjusted-p=0.06) and pseudouridine with higher risk (OR=9.84, 95%CI=2.89-37.82; p<0.001/adjusted-p=0.07) of non-serous tumors. Seven WGCNA modules and 15 classes were associated with risk at FDR[≤]0.20. Triacylglycerols (TAGs) showed heterogeneity by tumor aggressiveness (case-only heterogeneity-p<0.0001). TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. Pseudouridine may be a novel risk factor for ovarian cancer. TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features. Validation in independent prospective studies and complementary experimental work to understand biological mechanisms is needed.

epidemiology↗

bioRxiv2018

netome: a computational framework for metabolite profiling and omics network analysis

SummaryAdvances in metabolomics technologies have enabled comprehensive analyses of associations between metabolites and human disease and have provided a means to study biochemical pathways and processes in detail using model systems. Liquid chromatography tandem mass spectrometry (LC-MS) is an analytical technique commonly used by metabolomics labs to measure hundreds of metabolites of known identity and thousands of \"peaks\" from yet to be identified compounds that are tracked by their measured masses and chromatographic retention times. netome is a computational framework that provides tools for analyzing processed LC-MS data. In this framework, we develop and provide various computational resources including individual software modules to inspect and adjust trends in raw data, align unknown peaks between separately acquired data sets, and to remove redundancies in nontargeted LC-MS data arising from multiple ionization products of a single metabolite. These tools are deployed through computing resources such as web servers and virtual machines with detailed documentation in order to support researchers.\n\nAvailability and implementationnetome is publicly available with extensive documentation and support via issue tracker at https://broadinstitute.github.io/netome under the MIT license. netome includes a set of computational methods that have been designed to execute quality control and post-raw data processing tasks for metabolomics data (e.g. scaling and clustering metabolite abundances), as well as statistical association testing in a network manner (e.g., testing relationship between metabolites and microbes). Each individual tool is available with source code, workshop-oriented documentation which includes instructions for installation and using tools with demonstration examples, and a web server with all services. We also provide a complete image of the netome package with all pre-installed dependencies and support for Google Compute Engine and Amazon EC2. All tools and related services are maintained, and upon new developments, new modules will be added to the environment.\n\nContactrah@broadinstitute.org, clary@broadinstitute.org\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗