Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.

The role of bone marrow adipocytes in cancer progression: the impact of obesity.

Bone marrow adipose tissues (BMATs) and their main cellular component, bone marrow adipocytes (BMAds), are found within the bone marrow (BM), which is a niche for the development of hematological malignancies as well as bone metastasis from solid tumors such as breast and prostate cancers. In humans, BMAds are present within the hematopoietic or "red" BMAT and in the "yellow" BMAT where they are more densely packed. BMAds are emerging as new actors in tumor progression; however, there are many outstanding questions regarding their precise role. In this review, we summarized our current knowledge regarding the development, distribution, and regulation by external stimuli of the BMATs in mice and humans and addressed how obesity could affect these traits. We then discussed the specific metabolic phenotype of BMAds that appear to be different from "classical" white adipocytes, since they are devoid of lipolytic function. According to this characterization, we presented how tumor cells affect the in vitro and in vivo phenotype of BMAds and the signals emanating from BMAds that are susceptible to modulate tumor behavior with a specific emphasis on their metabolic crosstalk with cancer cells. Finally, we discussed how obesity could affect this crosstalk. Deciphering the role of BMAds in tumor progression would certainly lead to the identification of new targets in oncology in the near future.

SigB modulates expression of novel SigB regulon members via Bc1009 in non-stressed and heat-stressed cells revealing its alternative roles in Bacillus cereus.

BACKGROUND: The Bacillus cereus Sigma B (SigB) dependent general stress response is activated via the two-component RsbKY system, which involves a phosphate transfer from RsbK to RsbY. It has been hypothesized that the Hpr-like phosphocarrier protein (Bc1009) encoded by bc1009 in the SigB gene cluster may play a role in this transfer, thereby acting as a regulator of SigB activation. Alternatively, Bc1009 may be involved in the activation of a subset of SigB regulon members. RESULTS: We first investigated the potential role of bc1009 to act as a SigB regulator but ruled out this possibility as the deletion of bc1009 did not affect the expression of sigB and other SigB gene cluster members. The SigB-dependent functions of Bc1009 were further examined in B. cereus ATCC14579 via comparative proteome profiling (backed up by transcriptomics) of wt, Δbc1009 and ΔsigB deletion mutants under heat stress at 42 °C. This revealed 284 proteins displaying SigB-dependent alterations in protein expression levels in heat-stressed cells, including a subgroup of 138 proteins for which alterations were also Bc1009-dependent. Next to proteins with roles in stress defense, newly identified SigB and Bc1009-dependent proteins have roles in cell motility, signal transduction, transcription, cell wall biogenesis, and amino acid transport and metabolism. Analysis of lethal stress survival at 50 °C after pre-adaptation at 42 °C showed intermediate survival efficacy of Δbc1009 cells, highest survival of wt, and lowest survival of ΔsigB cells, respectively. Additional comparative proteome analysis of non-stressed wt and mutant cells at 30 °C revealed 96 proteins with SigB and Bc1009-dependent differences in levels: 51 were also identified under heat stress, and 45 showed significant differential expression at 30 °C. This includes proteins with roles in carbohydrate/ion transport and metabolism. Overlapping functions at 30 °C and 42 °C included proteins involved in motility, and ΔsigB and Δbc1009 cells showed reduced motility compared to wt cells in swimming assays at both temperatures. CONCLUSION: Our results extend the B. cereus SigB regulon to > 300 members, with a novel role of SigB-dependent Bc1009 in the activation of a subregulon of  > 180 members, conceivably via interactions with other transcriptional regulatory networks.

Mitochondrial plasticity in cell fate regulation.

Mitochondria are considered highly plastic organelles. This plasticity enables the mitochondria to undergo morphological and functional changes in response to cellular demands. Stem cells also need to remain functionally plastic (i.e. to have the ability to "decide" whether to remain quiescent or to undergo activation upon signaling cues to support tissue function and homeostasis). Mitochondrial plasticity is thought to enable this reshaping of stem cell functions, integrating signaling cues with stem cell outcomes. Indeed, recent evidence highlights the crucial role of maintaining mitochondrial plasticity for stem cell biology. For example, tricarboxylic acid (TCA) cycle metabolites generated and metabolized in the mitochondria serve as cofactors for epigenetic enzymes, thereby coupling mitochondrial metabolism and transcriptional regulation. Another layer of mitochondrial plasticity has emerged, pointing toward mitochondrial dynamics in regulating stem cell fate decisions. Imposing imbalanced mitochondrial dynamics by manipulating the expression levels of the key molecular regulators of this process influences cellular outcomes by changing the nuclear transcriptional program. Moreover, reactive oxygen species have also been shown to play an important role in regulating transcriptional profiles in stem cells. In this review, we focus on recent findings demonstrating that mitochondria are essential regulators of stem cell activation and fate decisions. We also discuss the suggested mechanisms and alternative routes for mitochondria-to-nucleus communications.

Proteomics insights into the effects of MSTN on muscle glucose and lipid metabolism in genetically edited cattle.

The molecular mechanism underlying myostatin (MSTN)-regulated metabolic cross-talk remains poorly understood. In this study, we performed comparative proteomic and phosphoproteomic analyses of gluteus muscle tissues from MSTN-/- transgenic cattle using a shotgun-based tandem mass tag (TMT) 6-plex labeling method to explore the signaling pathway of MSTN in metabolic cross-talk and cellular metabolism during muscle development. A total of 72 differentially expressed proteins (DEPs) and 36 differentially expressed phosphoproteins (DEPPs) were identified in MSTN-/- cattle compared to wild-type cattle. Bioinformatics analyses showed that MSTN knockout increased the activity of many key enzymes involved in fatty acid ß-oxidation and glycolysis processes in cattle. Furthermore, comprehensive pathway analyses and hypothesis-driven AMP-activated protein kinase (AMPK) activity assays suggested that MSTN knockout triggers the activation of AMPK signaling pathways to regulate glucose and lipid metabolism by increasing the AMP/ATP ratio. Our results shed new light on the potential regulatory mechanism of MSTN associated with metabolic cross-talk in muscle development, which can be used in animal breeding to improve meat production in livestock animals, and can also provide valuable insight into treatments for obesity and diabetes mellitus in humans.

Irisin interaction with adipose tissue secretions by exercise training and flaxseed oil supplement.

BACKGROUND: Previous studies have shown that physical training and natural diet able to change the expression and concentration of peptides and proteins. Myokines and adipokines play an important role in metabolism and metabolic syndrome. Therefore, the purpose of the present study was to investigate the effect of high-intensity interval training (HIIT) and supplementation of flaxseed oil on plasma irisin, nesfatin-1 and resistin in male rats. METHODS: Forty adult male rats were randomly divided into four groups (ten in each group) including Control-Saline (CS), Training-Saline (TS), Control-FlaxOil supplement (CO), and Training-FlaxOil supplement (TO). The training groups performed for 10 weeks and 5 sessions each week, interval training with 90-95% VO2max on rodent treadmill, and supplement groups received flaxseed oil (300 mg / kg). Five days after the last training session, rats were sacrificed. Blood samples were taken from the heart and plasma was evaluated. RESULTS: Exercise Training significantly increased plasma levels of irisin (P = 0.019), nesfatin-1 (P = 0.01), and decreased resistin (P = 0.01). Flaxseed oil significantly reduced plasma resistin levels (P = 0.02). Plasma irisin levels in the supplementation group were higher than all groups (P = 0.041). CONCLUSION: There was a significant positive correlation between plasma levels of irisin with nesfatin-1 and negative correlation with resistin. HIIT program with flaxseed oil as a modality can create a metabolic crosstalk between skeletal muscle and adipose tissues and have health benefits.

Total body exposure to low-dose ionizing radiation induces long-term alterations to the liver proteome of neonatally exposed mice.

Tens of thousands of people are being exposed daily to environmental low-dose gamma radiation. Epidemiological data indicate that such low radiation doses may negatively affect liver function and result in the development of liver disease. However, the biological mechanisms behind these adverse effects are unknown. The aim of this study was to investigate radiation-induced damage in the liver after low radiation doses. Neonatal male NMRI mice were exposed to total body irradiation on postnatal day 10 using acute single doses ranging from 0.02 to 1.0 Gy. Early (1 day) and late (7 months) changes in the liver proteome were tracked using isotope-coded protein label technology and quantitative mass spectrometry. Our data indicate that low and moderate radiation doses induce an immediate inhibition of the glycolysis pathway and pyruvate dehydrogenase availability in the liver. Furthermore, they lead to significant long-term alterations in lipid metabolism and increased liver inflammation accompanying inactivation of the transcription factor peroxisome proliferator-activated receptor alpha. This study contributes to the understanding of the potential risk of liver damage in populations environmentally exposed to ionizing radiation.

Tumor metabolic crosstalk and immunotherapy.

Tumor cells must resist the host's immune system while maintaining growth under harsh conditions of acidity and hypoxia, which indicates that tumors are more robust than normal tissue. Immunotherapeutic agents have little effect on solid tumors, mostly because of the tumor density and the difficulty of penetrating deeply into the tissue to achieve the theoretical therapeutic effect. Various therapeutic strategies targeting the tumor microenvironment (TME) have been developed. Immunometabolic disorders play a dominant role in treatment resistance at both the TME and host levels. Understanding immunometabolic factors and their treatment potential may be a way forward for tumor immunotherapy. Here, we summarize the metabolism of substances that affect tumor progression, the crosstalk between the TME and immunosuppression, and some potential tumor-site targets. We also summarize the progress and challenges of tumor immunotherapy.

Metabolic heterogeneity in tumor microenvironment - A novel landmark for immunotherapy.

The surrounding non-cancer cells and tumor cells that make up the tumor microenvironment (TME) have various metabolic rhythms. TME metabolic heterogeneity is influenced by the intricate network of metabolic control within and between cells. DNA, protein, transport, and microbial levels are important regulators of TME metabolic homeostasis. The effectiveness of immunotherapy is also closely correlated with alterations in TME metabolism. The response of a tumor patient to immunotherapy is influenced by a variety of variables, including intracellular metabolic reprogramming, metabolic interaction between cells, ecological changes within and between tumors, and general dietary preferences. Although immunotherapy and targeted therapy have made great strides, their use in the accurate identification and treatment of tumors still has several limitations. The function of TME metabolic heterogeneity in tumor immunotherapy is summarized in this article. It focuses on how metabolic heterogeneity develops and is regulated as a tumor progresses, the precise molecular mechanisms and potential clinical significance of imbalances in intracellular metabolic homeostasis and intercellular metabolic coupling and interaction, as well as the benefits and drawbacks of targeted metabolism used in conjunction with immunotherapy. This offers insightful knowledge and important implications for individualized tumor patient diagnosis and treatment plans in the future.

The metabolic crosstalk of cancer-associated fibroblasts and tumor cells: Recent advances and future perspectives.

Tumor cells grow in a microenvironment with a lack of nutrients and oxygen. Cancer-associated fibroblasts (CAFs) as one major component of tumor microenvironment have strong ability to survive under stressful conditions through metabolic remodelling. Furthermore, CAFs are educated by tumor cells and help them adapt to the hostile microenvironment through their metabolic communication. By inducing catabolism, CAFs release nutrients into the microenvironment which are taken up by tumor cells to satisfy their metabolic requirements. Furthermore, CAFs can recycle toxic metabolic wastes produced by cancer cells into energetic substances, allowing cancer cells to undergo biosynthesis. Their metabolic crosstalk also enhances CAFs' pro-tumor phenotype and reshape the microenvironment facilitating tumor cells' metastasis and immune escape. In this review, we have analyzed the effect and mechanisms of metabolic crosstalk between tumor cells and CAFs. We also analyzed the future perspectives in this area from the points of CAFs heterogeneity, spatial metabonomics and patient-derived tumor organoids (PDOs). These information may deepen the knowledge of tumor metabolism regulated by CAFs and provide novel insights into the development of metabolism-based anti-cancer strategies.

Deciphering metabolic crosstalk in context: lessons from inflammatory diseases.

Metabolism plays a crucial role in regulating the function of immune cells in both health and disease, with altered metabolism contributing to the pathogenesis of cancer and many inflammatory diseases. The local microenvironment has a profound impact on the metabolism of immune cells. Therefore, immunological and metabolic heterogeneity as well as the spatial organization of cells in tissues should be taken into account when studying immunometabolism. Here, we highlight challenges of investigating metabolic communication. Additionally, we review the capabilities and limitations of current technologies for studying metabolism in inflamed microenvironments, including single-cell omics techniques, flow cytometry-based methods (Met-Flow, single-cell energetic metabolism by profiling translation inhibition (SCENITH)), cytometry by time of flight (CyTOF), cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), and mass spectrometry imaging. Considering the importance of metabolism in regulating immune cells in diseased states, we also discuss the applications of metabolomics in clinical research, as well as some hurdles to overcome to implement these techniques in standard clinical practice. Finally, we provide a flowchart to assist scientists in designing effective strategies to unravel immunometabolism in disease-relevant contexts.

Targeted Mevalonate Pathway and Autophagy in Antitumor Immunotherapy.

Tumors of the digestive system are currently one of the leading causes of cancer-related death worldwide. Despite considerable progress in tumor immunotherapy, the prognosis for most patients remains poor. In the tumor microenvironment (TME), tumor cells attain immune escape through immune editing and acquire immune tolerance. The mevalonate pathway and autophagy play important roles in cancer biology, antitumor immunity, and regulation of the TME. In addition, there is metabolic crosstalk between the two pathways. However, their role in promoting immune tolerance in digestive system tumors has not previously been summarized. Therefore, this review focuses on the cancer biology of the mevalonate pathway and autophagy, the regulation of the TME, metabolic crosstalk between the pathways, and the evaluation of their efficacy as targeted inhibitors in clinical tumor immunotherapy.

Methyl-Jasmonate Functions as a Molecular Switch Promoting Cross-Talk between Pathways for the Biosynthesis of Isoprenoid Backbones Used to Modify Proteins in Plants.

In plants, the plastidial mevalonate (MVA)-independent pathway is required for the modification with geranylgeranyl groups of CaaL-motif proteins, which are substrates of protein geranylgeranyltransferase type-I (PGGT-I). As a consequence, fosmidomycin, a specific inhibitor of 1-deoxy-d-xylulose (DX)-5 phosphate reductoisomerase/DXR, the second enzyme in this so-called methylerythritol phosphate (MEP) pathway, also acts as an effective inhibitor of protein prenylation. This can be visualized in plant cells by confocal microscopy by expressing GFP-CaM-CVIL, a prenylation sensor protein. After treatment with fosmidomycin, the plasma membrane localization of this GFP-based sensor is altered, and a nuclear distribution of fluorescence is observed instead. In tobacco cells, a visual screen of conditions allowing membrane localization in the presence of fosmidomycin identified jasmonic acid methyl esther (MeJA) as a chemical capable of gradually overcoming inhibition. Using Arabidopsis protein prenyltransferase loss-of-function mutant lines expressing GFP-CaM-CVIL proteins, we demonstrated that in the presence of MeJA, protein farnesyltransferase (PFT) can modify the GFP-CaM-CVIL sensor, a substrate the enzyme does not recognize under standard conditions. Similar to MeJA, farnesol and MVA also alter the protein substrate specificity of PFT, whereas DX and geranylgeraniol have limited or no effect. Our data suggest that MeJA adjusts the protein substrate specificity of PFT by promoting a metabolic cross-talk directing the origin of the prenyl group used to modify the protein. MVA, or an MVA-derived metabolite, appears to be a key metabolic intermediate for this change in substrate specificity.

Pancreatic stellate cells exploit Wnt/ß-catenin/TCF7-mediated glutamine metabolism to promote pancreatic cancer cells growth.

Pancreatic stellate cells (PSCs) are crucial for metabolism and disease progression in pancreatic ductal adenocarcinoma (PDAC). However, detailed mechanisms of PSCs in glutamine (Gln) metabolism and tumor-stromal metabolic interactions have not been well clarified. Here we showed that tumor tissues displayed Gln deficiency in orthotopic PDAC models. Single-cell RNA sequencing analysis revealed metabolic heterogeneity in PDAC, with significantly higher expression of Gln catabolism pathway in stromal cells. Significantly higher glutamine synthetase (GS) protein expression was further validated in human tissues and cells. Elevated GS levels in tumor and stroma were independently prognostic of poorer prognosis in PDAC patients. Gln secreted by PSCs increased basal oxygen consumption rate in PCCs. Depletion of GS in PSCs significantly decreased PCCs proliferation in vitro and in vivo. Mechanistically, activation of Wnt signaling induced directly binding of ß-catenin/TCF7 complex to GS promoter region and upregulated GS expression. Rescue experiments testified that GS overexpression recovered ß-catenin knockdown-mediated function on Gln synthesis and tumor-promoting ability of PSCs. Overall, these findings identify the Wnt/ß-catenin/TCF7/GS-mediated growth-promoting effect of PSCs and provide new insights into stromal Gln metabolism, which may offer novel therapeutic strategies for PDAC.

Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration.

Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.

Host species shape the community structure of culturable endophytes in fruits of wild berry species (Vaccinium myrtillus L., Empetrum nigrum L. and Vaccinium vitis-idaea L.).

Wild berries are interesting research subjects due to their rich sources of health-beneficial phenolic compounds. However, the internal microbial communities, endophytes, associated with the wild berry fruits are currently unknown. Endophytes are bacteria or fungi inhabiting inside plant tissues, and their functions vary depending on the host species and environmental parameters. The present study aimed to examine community composition of fungal and bacterial endophytes in fruits of three wild berry species (bilberry Vaccinium myrtillus L., lingonberry Vaccinium vitis-idaea L. and crowberry Empetrum nigrum L.) and the effects of host plant species and their growth sites on shaping the endophytic communities. We found that the endophytic community structures differed between the berry species, and fungi were predominant over bacteria in the total endophytic taxa. We identified previously unknown endophytic fungal taxa including Angustimassarina, Dothidea, Fellozyma, Pseudohyphozyma, Hannaella coprosmae and Oberwinklerozyma straminea. A role of soluble phenolic compounds, the intracellular components in wild berry fruits, in shaping the endophytic communities is proposed. Overall, our study demonstrates that each berry species harbors a unique endophytic community of microbes.

Genome Scale Modeling to Study the Metabolic Competition between Cells in the Tumor Microenvironment.

The tumor's physiology emerges from the dynamic interplay of numerous cell types, such as cancer cells, immune cells and stromal cells, within the tumor microenvironment. Immune and cancer cells compete for nutrients within the tumor microenvironment, leading to a metabolic battle between these cell populations. Tumor cells can reprogram their metabolism to meet the high demand of building blocks and ATP for proliferation, and to gain an advantage over the action of immune cells. The study of the metabolic reprogramming mechanisms underlying cancer requires the quantification of metabolic fluxes which can be estimated at the genome-scale with constraint-based or kinetic modeling. Constraint-based models use a set of linear constraints to simulate steady-state metabolic fluxes, whereas kinetic models can simulate both the transient behavior and steady-state values of cellular fluxes and concentrations. The integration of cell- or tissue-specific data enables the construction of context-specific models that reflect cell-type- or tissue-specific metabolic properties. While the available modeling frameworks enable limited modeling of the metabolic crosstalk between tumor and immune cells in the tumor stroma, future developments will likely involve new hybrid kinetic/stoichiometric formulations.

Drilling for Oil: Tumor-Surrounding Adipocytes Fueling Cancer.

Over the past decade, it has become apparent that metabolic reprogramming is a key event in tumor progression. The tumor microenvironment (TME) is a source of metabolites for tumor cells. Lipid-filled mature adipocytes are frequently found in proximity to invasive human tumors and release free fatty acids (FFAs) through lipolysis. These FFAs are taken up by tumor cells and used to promote tumor progression by mechanisms that include mitochondrial fatty acid oxidation (FAO). This review discusses recent advances in our understanding of this metabolic symbiosis between adipocytes and cancer cells and underlines the differences in this metabolic crosstalk between the various types of cancer and their localization.

Metabolic reprograming of tumor-associated macrophages.

A large body of scientific evidence corroborated by clinical and animal model experiments indicates that tumor-associated macrophages (TAMs) play a crucial role in tumor development and progression. TAMs are a key immune cell type present in tumor microenvironment (TME) and associated with poor prognosis, drug resistance, enhanced angiogenesis and metastasis in cancer. TAMs are a phenotypically diverse population of myeloid cells which display tremendous plasticity and dynamic metabolic nature. A complete interpretation of pro-tumoral and anti-tumoral metabolic switch in TAMs is essential to understand immune evasion mechanisms in cancer. Recent studies have also implicated epigenetic mechanisms as significantly regulators of TAM functions. In this review we provide an overview of metabolic circuitry in TAMs, its impact on immune effector cells and interventions aimed at rewiring the metabolic circuits in TAMs. Mechanisms responsible for TAM polarization in cancer are also discussed.