Biology subjects

Huan, T.

Publications and source records attributed to Huan, T..

At least 19 recordsLinked to original sources

bioRxiv2026

FeatureMSEA: Metabolic Feature-based Metabolite Set Enrichment Analysis

Liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics detects thousands of metabolic features, but converting these chemical signals into metabolite set-level biological knowledge remains challenging. This is because most features lack unambiguous metabolite identities. Conventional metabolite set enrichment analysis (MSEA) generally requires identified metabolites and metabolite-level ranked inputs, leaving much of the untargeted feature space unused. Here, we present FeatureMSEA, a feature rank-based framework for metabolite set enrichment directly from metabolic features with ambiguous annotations. FeatureMSEA integrates multi-evidence feature-to-metabolite annotation, feature rank-based enrichment scoring, permutation-based inference, and iterative leading-edge-guided annotation refinement, with an optional LLM-assisted module for post-enrichment interpretation. In null comparisons of randomly split healthy samples, FeatureMSEA detected no significant metabolite sets, whereas metabolite-set spike-in simulations showed recovery of implanted signals. In a cerebrospinal fluid metabolomics study of Huntingtons disease, FeatureMSEA identified dysregulated metabolite sets related to amino acid metabolism, mitochondrial energy metabolism, and neuroactive signaling. MS/MS-based annotation analysis further showed that FeatureMSEA refinement reduced annotation ambiguity and prioritized chemically consistent candidate metabolites. In summary, FeatureMSEA provides a general framework for extracting metabolite set-level biological insights from LC-MS untargeted metabolomics in which confident metabolite identification remains incomplete.

bioinformatics↗

bioRxiv2025

Maternal sucrose intake during pregnancy alone disrupts testosterone and allopregnanolone levels in the fetal brain of rats

BackgroundIntake of added sugars, such as sucrose, is high globally. In rats, a maternal high-sucrose diet (HSD) from 10 wk before pregnancy to embryonic day (E)19.5 has widespread impacts on maternal, placental, and fetal blood and brain steroid levels, including glucocorticoids, androgens, and aldosterone. ObjectiveThis study examined whether maternal HSD during pregnancy alone is sufficient to alter maternal, placental, and fetal steroids. MethodsPregnant rats received either a control diet (1% kcal sucrose) or an isocaloric, nutrient-matched HSD (26% kcal sucrose) between E0.5-19.5. On E19.5, we collected maternal serum, placenta, fetal blood and brain, and amniotic fluid. We microdissected the placenta and fetal brain and measured 14 steroids using highly sensitive and specific liquid chromatography-tandem mass spectrometry (n=12-15/diet/sex). ResultsMaternal HSD during pregnancy alone did not alter maternal food intake, maternal body mass, and litter size (all p values [≥] 0.29, Students t-test) but increased the percentage of males in a litter (p = 0.03, Students t-test). Maternal HSD did not alter steroids in the maternal serum (all p values [≥] 0.21, Students t-test), placenta (all p values [≥] 0.07, 2-way analysis of variance (ANOVA)), and fetal blood (all p values [≥] 0.13, 2-way ANOVA). Nonetheless, maternal HSD increased testosterone in the fetal nucleus accumbens (p = 0.04, 2-way ANOVA), decreased allopregnanolone in the fetal amygdala (p = 0.01, 2-way ANOVA), and decreased 11-dehydrocorticosterone in the amniotic fluid (p = 0.05, 2-way ANOVA). ConclusionsMaternal HSD during pregnancy alone does not affect steroid levels in the maternal serum, placenta, or fetal blood, but disrupts testosterone and allopregnanolone levels in critical regions of the fetal brain that regulate reward-seeking and emotion. Thus, while a long-term maternal HSD is necessary for widespread endocrine effects, the fetal brain is sensitive to short-term increases in maternal sucrose consumption during pregnancy.

neuroscience↗

bioRxiv2024

Insulin/insulin-like growth factor signaling pathway promotes higher fat storage in Drosophila females

In Drosophila, adult females store more fat than males. While the mechanisms that restrict body fat in males are becoming clearer, less is known about how females achieve higher fat storage. Here, we perform a detailed investigation of the mechanisms that promote higher fat storage in females. We show greater intake of dietary sugar supports higher fat storage due to female-biased remodeling of the fat body lipidome. Dietary sugar stimulates a female-specific increase in Drosophila insulin-like peptide 3 (Dilp3), which acts together with greater peripheral insulin sensitivity to augment insulin/insulin-like growth factor signaling pathway (IIS) activity in adult females. Indeed, Dilp3 overexpression prevented the female-biased decrease in body fat after removal of dietary sugar. Given that adult-specific IIS inhibition caused a female-biased decrease in body fat, our data reveal IIS as a key determinant of female fat storage.

physiology↗

bioRxiv2024

Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis

ABSTRACTLipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo. We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease. HIGHLIGHTSO_LILipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene network C_LIO_LINeuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasis C_LIO_LILD regulation supports ER and mitochondrial function in hunger-activated neurons C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/613929v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1936e92org.highwire.dtl.DTLVardef@40478aorg.highwire.dtl.DTLVardef@18d5faorg.highwire.dtl.DTLVardef@882ee9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Early life intestinal inflammation alters gut microbiome, impairing gut-brain communication and reproductive behavior in mice

Despite recent advances in understanding the connection between the gut microbiota and the adult brain, there remains a wide knowledge gap in how gut inflammation impacts brain development. We hypothesized that intestinal inflammation in early life would negatively affect neurodevelopment through dysregulation of microbiota communication to the brain. We therefore developed a novel pediatric chemical model of inflammatory bowel disease (IBD), an incurable condition affecting millions of people worldwide. IBD is characterized by chronic intestinal inflammation, and has comorbid symptoms of anxiety, depression and cognitive impairment. Significantly, 25% of patients with IBD are diagnosed during childhood, and the effect of chronic inflammation during this critical period of development is largely unknown. This study investigated the effects of early-life gut inflammation induced by DSS (dextran sulfate sodium) on a range of microbiota, endocrine, and behavioral outcomes, focusing on sex-specific impacts. DSS-treated mice exhibited increased intestinal inflammation, altered microbiota membership, and changes in microbiota-mediated circulating metabolites. The majority of behavioral measures were unaffected, with the exception of impaired mate-seeking behaviors in DSS-treated males. DSS-treated males also showed significantly smaller seminal vesicles, lower circulating androgens, and decreased intestinal hormone-activating enzyme activity. In the brain, microglia morphology was chronically altered with DSS treatment in a sex-specific manner. The results suggest that early-life gut inflammation causes changes in gut microbiota composition, affecting short-chain fatty acid (SCFA) producers and glucuronidase (GUS) activity, correlating with altered SCFA and androgen levels. The findings emphasize the developmental sensitivity to inflammation-induced changes in endocrine signalling and underscore long-lasting physiological and microbiome changes associated with juvenile IBD. HighlightsEarly-life gut inflammation produces sex-specific effects on i) microbiome, ii) sex hormones and iii) behaviour. Both sexes show disrupted gut bacterial members that regulate sex hormone levels. Male mice demonstrate deficits in mate seeking, which may be mediated by reduced androgen levels. Both male and female mice demonstrate shifts in hippocampal microglial morphology.

neuroscience↗

bioRxiv2023

Bayesian optimization of separation gradients to maximize the performance of untargeted LC-MS

Liquid chromatography (LC) with gradient elution is a routine practice for separating complex chemical mixtures in mass spectrometry (MS)-based untargeted analysis. Despite its prevalence, systematic optimization of LC gradients has remained challenging. Here we develop a Bayesian optimization method, BAGO, for autonomous and efficient LC gradient optimization. BAGO is an active learning strategy that discovers the optimal gradient using limited experimental data. From over 100,000 plausible gradients, BAGO locates the optimal LC gradient within ten sample analyses. We validated BAGO on six biological studies of different sample matrices and LC columns, showing that BAGO can significantly improve quantitative performance, tandem MS spectral coverage, and spectral purity. For instance, the optimized gradient increases the count of annotated compounds meeting quantification criteria by up to 48.5%. Furthermore, applying BAGO in a Drosophila metabolomics study, an additional 57 metabolites and 126 lipids were annotated. The BAGO algorithms were implemented into user-friendly software for everyday laboratory practice and a Python package for its flexible extension.

bioinformatics↗

bioRxiv2022

An important role for triglyceride in regulating spermatogenesis

Drosophila is a powerful model to study how lipids affect spermatogenesis. Yet, the contribution of neutral lipids, a major lipid group which resides in organelles called lipid droplets (LD), to sperm development is largely unknown. Emerging evidence suggests LD are present in the testis and that loss of neutral lipid- and LD-associated genes causes subfertility; however, key regulators of testis neutral lipids and LD remain unclear. Here, we show LD are present in early-stage somatic and germline cells within the Drosophila testis. We identified a role for triglyceride lipase brummer (bmm) in regulating testis LD, and found that whole-body loss of bmm leads to defects in sperm development. Importantly, these represent cell-autonomous roles for bmm in regulating testis LD and spermatogenesis. Because lipidomic analysis of bmm mutants revealed excess triglyceride accumulation, and spermatogenic defects in bmm mutants were rescued by genetically blocking triglyceride synthesis, our data suggest that bmm-mediated regulation of triglyceride influences sperm development. This identifies triglyceride as an important neutral lipid that contributes to Drosophila sperm development, and reveals a key role for bmm in regulating testis triglyceride levels during spermatogenesis.

developmental biology↗

bioRxiv2022

The cell envelope of Thermotogae suggests a mechanism for outer membrane biogenesis

The presence of a cell membrane is one of the major structural components defining life. Recent phylogenomic analyses have supported the hypothesis that the last bacterial common ancestor was likely a diderm. Yet, the mechanisms that guided outer membrane (OM) biogenesis remain unknown. Thermotogae is an early-branching phylum with a unique OM, the toga, previously shown to form 2-dimensional arrays of {beta}-barrel trimers. Here we use cryo-electron tomography to characterize the in situ cell envelope architecture of Thermotoga maritima, proteomics and lipidomics to identify the protein and lipid composition of the toga, and bioinformatics to assess the distribution of the major toga components across the phylum. We show that the toga is composed of multiple Omp and {beta}-barrel homologs that represent a highly diverse bipartite OM-tethering system. We further reveal the presence of membrane microdomains ([~]200nm) in the toga that are enriched in phosphatidylethanolamine (PE) lipids required to support the type 4 pilus and the BamA transmembrane complexes. Together, our results highlight a toga-like structure as a possible intermediate between monoderm and diderm cell envelope transitions.

microbiology↗

bioRxiv2022

Molecular formula discovery via bottom-up MS/MS interrogation

A substantial fraction of metabolic features remains undetermined in mass spectrometry (MS)-based metabolomics. Here we present bottom-up tandem MS (MS/MS) interrogation to illuminate the unidentified features via accurate molecular formula annotation. Our approach prioritizes MS/MS-explainable formula candidates, implements machine-learned ranking, and offers false discovery rate estimation. Compared to the existing MS1-initiated formula annotation, our approach shrinks the formula candidate space by 42.8% on average. The superior annotation accuracy of our bottom-up interrogation was demonstrated on reference MS/MS libraries and real metabolomics datasets. Applied on 155,321 annotated recurrent unidentified spectra (ARUS), our approach confidently annotated >5,000 novel molecular formulae unarchived in chemical databases. Beyond the level of individual metabolic features, we combined bottom-up MS/MS interrogation with global peak annotation. This approach reveals peak interrelationships, allowing the systematic annotation of 37 fatty acid amide molecules in human fecal data, among other applications. All bioinformatics pipelines are available in a standalone software, BUDDY (https://github.com/HuanLab/BUDDY/).

bioinformatics↗

bioRxiv2022

Multi-omic profiling of the leukemic microenvironment shows bone marrow interstitial fluid is distinct from peripheral blood plasma

The bone marrow is the place of hematopoiesis with a microenvironment that supports lifelong maintenance of stem cells and high proliferation. It is not surprising that this environment is also favourable for malignant cells emerging in the bone marrow or metastasizing to it. While the cellular composition of the bone marrow microenvironment has been extensively studied, the extracellular matrix and interstitial fluid components have received little attention. Since the sinusoids connect the bone marrow interstitial fluid to the circulation, it is often considered to have the same composition as peripheral blood plasma. Stark differences in the cellular composition of the bone marrow and peripheral blood with different secretory capacities would however suggest profound differences. In this study we set out to better define if and how the bone marrow interstitial fluid (BMIF) compares to the peripheral blood plasma (PBP) and how both are remodeled during chemotherapy. We applied a multi-omic strategy to quantify the metabolite, lipid and protein components as well as the proteolytic modification of proteins to gain a comprehensive understanding of the two compartments. We found that the bone marrow interstitial fluid is clearly distinct from peripheral blood plasma, both during active pediatric acute lymphoblastic leukemia and following induction chemotherapy. Either compartment was shaped differently by active leukemia, with the bone marrow interstitial fluid being rich in extracellular vesicle components and showing protease dysregulation while the peripheral blood plasma showed elevation of immune regulatory proteins. Following chemotherapy, the BMIF showed signs of cellular remodeling and impaired innate immune activation while the peripheral blood plasma was characterized by restored lipid homeostasis.

cancer biology↗

bioRxiv2021

MAFFIN: Metabolomics Sample Normalization Using Maximal Density Fold Change with High-Quality Metabolic Features and Corrected Signal Intensities

Sample normalization is a critical step in metabolomics to remove differences in total sample amount or concentration of metabolites between biological samples. Here, we present MAFFIN, an accurate and robust post-acquisition sample normalization workflow that works universally for metabolomics data collected by mass spectrometry (MS)-based platforms. The most important design of MAFFIN is the calculation of normalization factor using maximal density fold change (MDFC) value computed by a kernel density-based approach. MDFC is more accurate than traditional median FC-based normalization, especially when the numbers of up- and down-regulated metabolic features are different. In addition, we showcase two essential steps that are overlooked by conventional normalization methods, and incorporated them into MAFFIN. First, instead of using all detected metabolic features, MAFFIN automatically extracts and uses only the high-quality features to calculate FCs and determine the normalization factor. In particular, multiple orthogonal criteria are proposed to pick up the high-quality features. Second, to guarantee the accuracy of the FCs, the MS signal intensities of the high-quality features are corrected using serial quality control (QC) samples. Using simulated data and urine metabolomics datasets, we demonstrated the critical need of high-quality feature selection, MS signal correction, and MDFC. We also show the superior performance of MAFFIN over other commonly used post-acquisition sample normalization methods. Finally, a biological application on a human saliva metabolomics study shows that MAFFIN provides robust sample normalization, leading to better data separation in principal component analysis (PCA) and the identification of more significantly altered metabolic features. TOC O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

bioinformatics↗

bioRxiv2020

Cardiovascular Disease Related Proteomic Biomarkers of Alcohol Consumption

The relationship between alcohol consumption, circulating proteins, and cardiovascular disease (CVD) risk has not been well studied. We performed association analyses of alcohol consumption with three CVD risk factors and 71 CVD-related circulating proteins measured in 6,745 Framingham Heart Study participants (mean age, 49 years; 53% women). We found that an increase in alcohol consumption was associated with a higher risk of incident hypertension (P=7.2E-3) but a lower risk of incident obesity (P=5.7E-4) and type 2 diabetes (P=1.4E-5) in a 14-year of follow-up. Using independent discovery (n=4,348) and validation (n=2,397) samples, we identified 20 alcohol-associated proteins (FDR<0.05 in discovery and P<0.05/n in validation), with majority (18 of 20 proteins) inversely associated with alcohol consumption. The alcohol-protein associations remained similar after removing heavy drinkers. Four proteins demonstrated consistent triangular relationships, as expected, with alcohol consumption and CVD risk factors. For example, a greater level of APOA1, which was associated with a higher alcohol consumption (P=1.2E-65), was associated with a lower risk of type 2 diabetes (P=3.1E-5). However, several others showed inconsistent triangular relationships, e.g., a greater level of GDF15, which was associated with a lower alcohol consumption (P=1.0E-13), was associated with an increased risk of hypertension (P=2.4E-4). In conclusion, we identified 20 alcohol-associated proteins and demonstrated complex relationships between alcohol consumption, circulating proteins and CVD risk factors. Future studies with integration of more proteomic markers and larger sample size are warranted to unravel the complex relationship between alcohol consumption and CVD risk.

bioinformatics↗

bioRxiv2020

No endospore formation confirmed in members of the phylum Proteobacteria

Endospore formation is used by members of the phylum Firmicutes to withstand extreme environmental conditions. Several recent studies have documented endospore formation in species outside of Firmicutes, particularly in Rhodobacter johrii and Serratia marcescens, members of the phylum Proteobacteria. Here, we aimed to investigate endospore formation in these two species by using advanced imaging and analytical approaches. Examination of the phase-bright structures observed in R. johrii and S. marcescens using cryo-electron tomography failed to identify endospores or stages of endospore formation. We determined that the phase-bright objects in R. johrii cells were triacylglycerol storage granules and those in S. marcescens were aggregates of cellular debris. In addition, R. johrii and S. marcescens containing phase-bright objects do not possess phenotypic and genetic features of endospores, including enhanced resistance to heat, presence of dipicolinic acid, or the presence of many of the genes associated with endospore formation. Our results support the hypothesis that endospore formation is restricted to the phylum Firmicutes. ImportanceEndospore formation is a mechanism that allows bacteria to generate resilient dormant spores under harsh environmental conditions. Although this process has been traditionally restricted to the largely Gram-positive bacteria of the phylum Firmicutes, recent studies have also described endospores in some Proteobacteria. High complexity of endosporulation, reflected in extensive morphological transformations governed by hundreds of conserved genes, hinders its facile acquisition via horizontal gene transfer. Therefore, ability of distantly related bacteria to produce endospores would imply an ancient nature of this mechanism and potentially a pivotal role in species diversification and outer membrane biogenesis.

microbiology↗

bioRxiv2019

RNA sequencing and lipidomic analysis of alveolar macrophages from normal and CD44 deficient mice

Alveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44-/- mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44-/- AMs had increased expression of CD36, a lipid scavenger receptor, as well as increased intracellular lipid droplets, giving them a foamy appearance. RNA sequencing revealed the differential expression of genes associated with lipid efflux and metabolism in CD44-/- AMs. Lipidomic analysis showed increased lipids in both the supernatant and cell pellet extracted from the bronchoalveolar lavage of CD44-/- mice. Phosphatidylcholine species, cholesterol, oxidized phospholipids and levels of reactive oxygen species (ROS) were increased in CD44-/- AMs. Oxidized phospholipids were more cytotoxic to CD44-/- AMs and induced greater lung inflammation in CD44-/- mice. Reconstitution of CD44+/+ mice with CD44-/- bone marrow as well as adoptive transfer of CD44-/- AMs into CD44+/+ mice showed that lipid accumulation in CD44-/- AMs occurred irrespective of the lung environment, suggesting a cell intrinsic defect. Administration of colony stimulating factor 2 (CSF-2), a critical factor in AM development and maintenance, increased AM numbers in CD44-/- mice and decreased phosphatidylcholine levels in the bronchoalveolar lavage, but was unable to decrease intracellular lipid accumulation in CD44-/- AMs. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}), downstream of CSF-2 signaling and a regulator of lipid metabolism, was reduced in the nucleus of CD44-/- AMs, and PPAR{gamma} inhibition in normal AMs increased their lipid droplets. Thus, CD44 deficiency causes defects in AMs that lead to abnormal lipid accumulation and oxidation, which exacerbates oxidized lipid-induced lung inflammation. Collectively, these findings implicate CD44 as a regulator of lung homeostasis and inflammation.

immunology↗

bioRxiv2019

Cariogenic Streptococcus mutans produces strain-specific antibiotics that impair commensal colonization

Streptococcus mutans is a common constituent of dental plaque and an etiologic agent of dental caries (tooth decay). Here we elucidate a biosynthetic pathway, encoded by globally distributed strains of S. mutans, which produces a series of bioactive small molecules including reutericyclin and two N-acyl tetramic acid analogues active against oral commensal bacteria. This pathway may provide S. mutans with a competitive advantage, promoting dysbiosis and caries pathogenesis.

microbiology↗

bioRxiv2019

Avant-garde assembly-line biosynthesis expands diversity of cyclic lipodepsipeptide products

Modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzymatic assembly lines are large and dynamic protein machines that generally undergo a linear progression of catalytic cycles via a series of enzymatic domains organized into independent modules. Here we report the heterologous reconstitution and comprehensive characterization of two hybrid NRPS-PKS assembly lines that defy many standard rules of assembly-line biosynthesis to generate a large combinatorial library of cyclic lipodepsipeptide protease inhibitors called thalassospiramides. We generate a series of precise domain-inactivating mutations in thalassospiramide assembly lines and present compelling evidence for an unprecedented biosynthetic model that invokes inter-module substrate activation and tailoring, module skipping, and pass-back chain extension, whereby the ability to pass the growing chain back to a preceding module is flexible and substrate-driven. Expanding bidirectional inter-module domain interactions could represent a viable mechanism for generating chemical diversity without increasing the size of biosynthetic assembly lines and raises new questions regarding our understanding of the structural features of multi-modular megaenzymes.

molecular biology↗

bioRxiv2017

Multiethnic Meta-analysis Identifies New Loci for Pulmonary Function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.

genetics↗

bioRxiv2017

Dietary xenoestrogens significantly alter cellular metabolism induced by palbociclib/letrozole combination cancer therapy

HighlightsO_LISynergism of combined palbociclib/letrozole chemotherapy was examined by global metabolomics\nC_LIO_LICombination therapy led to more pronounced effects on the MCF-7 metabolome than single agents\nC_LIO_LIDietary phyto- and mycoestrogens significantly affected the metabolic and anti-oncogenic response of the drugs\nC_LIO_LIImplications of these bio-active chemicals on therapeutic success in breast cancer patients appear plausible\nC_LI\n\nIn BriefWarth et al. used innovative global metabolomics and pathway prediction technology to describe the metabolic effects of the combined palbociclib/letrozole breast cancer therapy. Moreover, the role of dietary xenoestrogens on this treatment was examined by metabolite data, proliferation experiments, and functional assays.\n\nSummaryRecently, the palbociclib/letrozole combination therapy was granted accelerated FDA approval for the treatment of estrogen receptor (ER) positive breast cancer. Since the underlying metabolic effects of these drugs are yet unknown, we investigated their synergism at the metabolome level in MCF-7 cells. As xenoestrogens interact with the ER, we additionally aimed at deciphering the impact of the phytoestrogen genistein, and the estrogenic mycotoxin zearalenone on this treatment. A global metabolomics approach was applied to unravel metabolite and pathway modifications. The results clearly showed that the combined effects of palbociclib and letrozole on cellular metabolism were far more pronounced than that of each agent alone and potently influenced by xenoestrogens. This behavior was confirmed in proliferation experiments and functional assays. Specifically, amino acids and central carbon metabolites were attenuated while higher abundances were observed for fatty acids and most nucleic acid related metabolites. Interestingly, exposure to model xenoestrogens appeared to partially counteract these effects.

cancer biology↗