bims-medica 2024-03-10 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒03‒10
28 papers selected by
Brett Chrest, East Carolina University

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth.
A ketogenic diet rich in fish oil is superior to other fats in preventing NNK-induced lung cancer in A/J mice.
Glucose Metabolism in Acute Myeloid Leukemia Cell Line Is Regulated via Combinational PI3K/AKT/mTOR Pathway Inhibitors.
Ketogenic therapy towards precision medicine for brain diseases.
Everolimus decreases [U-13C]glucose utilization by pyruvate carboxylase in breast cancer cells in vitro and in vivo.
Current methods for hyperpolarized [1-13 C]pyruvate MRI human studies.
Postabsorptive and postprandial glucose and fat metabolism in postmenopausal women with breast cancer-Preliminary data after chemotherapy compared to healthy controls.
Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells.
A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
Targeting SHMTs and MTHFDs in cancer: attractive opportunity for anti-tumor strategy.
A miniaturized culture platform for control of the metabolic environment.
Mitochondrial ATP generation is more proteome efficient than glycolysis.
Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
Real-time resolution studies of the regulation of lactate production by hexokinases binding to mitochondria in single cells.
Not just sugar: Metabolic control of neutrophil development and effector functions.
Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
Mechanisms of resistance to venetoclax in hematologic malignancies.
Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.
How and When to Measure Mitochondrial Inner Membrane Potentials.
Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.
Literature review and expert opinion on the treatment of high-risk acute myeloid leukemia in patients who are eligible for intensive chemotherapy.
The impact of ketogenic diet on some metabolic and non-metabolic diseases: Evidence from human and animal model experiments.
Perceiving a need for dietary change in adults living with and beyond cancer: A cross-sectional study.
Mediterranean-style dietary interventions in adults with cancer: a systematic review of the methodological approaches, feasibility, and preliminary efficacy.
Lipid droplets and cellular lipid flux.
Body mass index, weight change, and cancer prognosis: a meta-analysis and systematic review of 73 cohort studies.
Butyrate's (a short-chain fatty acid) microbial synthesis, absorption, and preventive roles against colorectal and lung cancer.
Cellular senescence is associated with the spatial evolution toward a higher metastatic phenotype in colorectal cancer.

Innovation (Camb). 2024 Mar 04. 5(2): 100583

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth.

Johan Gustafsson, Fariba Roshanzamir, Anders Hagnestål, Sagar M Patel, Oseeyi I Daudu, Donald F Becker, Jonathan L Robinson, Jens Nielsen.

The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments.

DOI: https://doi.org/10.1016/j.xinn.2024.100583
Sci Rep. 2024 Mar 07. 14(1): 5610

A ketogenic diet rich in fish oil is superior to other fats in preventing NNK-induced lung cancer in A/J mice.

Ingrid Elisia, Michelle Yeung, Sara Kowalski, Taras Shyp, Jason Tee, Serena Hollman, Amy Wong, Janette King, Roger Dyer, Poul H Sorensen, Gerald Krystal.

  Given that ketogenic diets (KDs) are extremely high in dietary fat, we compared different fats in KDs to determine which was the best for cancer prevention. Specifically, we compared a Western and a 15% carbohydrate diet to seven different KDs, containing either Western fats or fats enriched in medium chain fatty acids (MCTs), milk fat (MF), palm oil (PO), olive oil (OO), corn oil (CO) or fish oil (FO) for their ability to reduce nicotine-derived nitrosamine ketone (NNK)-induced lung cancer in mice. While all the KDs tested were more effective at reducing lung nodules than the Western or 15% carbohydrate diet, the FO-KD was most effective at reducing lung nodules. Correlating with this, mice on the FO-KD had low blood glucose and the highest β-hydroxybutyrate level, lowest liver fatty acid synthase/carnitine palmitoyl-1a ratio and a dramatic increase in fecal Akkermansia. We found no liver damage induced by the FO-KD, while the ratio of total cholesterol/HDL was unchanged on the different diets. We conclude that a FO-KD is superior to KDs enriched in other fats in reducing NNK-induced lung cancer, perhaps by being the most effective at skewing whole-body metabolism from a dependence on glucose to fats as an energy source.

Keywords:  Fish oil; Glycolysis; Ketogenic diet; Low carbohydrate; Lung cancer

DOI:  https://doi.org/10.1038/s41598-024-55167-6
Iran J Pharm Res. 2023 Jan-Dec;22(1):22(1): e140507

Glucose Metabolism in Acute Myeloid Leukemia Cell Line Is Regulated via Combinational PI3K/AKT/mTOR Pathway Inhibitors.

Abbas Ranjbar, Mohsen Soltanshahi, Saeid Taghiloo, Hossein Asgarian-Omran.

  Background: Metabolism reprogramming is a survival mechanism in acute myeloid leukemia (AML) cells in the tumor microenvironment. Therefore, we investigated the effect of signaling pathway inhibitors on the expression of genes rewired in the metabolic pathway of AML cells.Methods: HL-60 cells were treated with Idelalisib, MK-2206, and Everolimus, which respectively are selective inhibitors of phosphatidylinositol-3-kinase (PI3K), AKT, and the mammalian target of rapamycin (mTOR), either individually or in combination. The relative expressions of glucose transporter 1, hexokinase 2, pyruvate kinase, pyruvate dehydrogenase E1, citrate synthase, isocitrate dehydrogenase 2, and hypoxia inducible factor 1 subunit alpha were determined by real-time PCR.
Results: The combined treatment of HL-60 cells with Idelalisib, MK-2206, and Everolimus decreased the expression of glucose transporter 1, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase E1, citrate synthase, isocitrate dehydrogenase 2, and hypoxia inducible factor 1 subunit alpha.
Conclusions: A combination of PI3K/AKT/mTOR pathway inhibitors regulates the expression of genes involved in glycolysis, pyruvate dehydrogenase complex (PDH), and the tricarboxylic acid (TCA) cycle and interferes with metabolic reprogramming and immune evasion mechanisms of AML leukemic cells. Combinational therapy approaches to block these pathways might be a promising and novel therapeutic strategy for targeting the metabolic requirements of AML cells.

Keywords:  Acute Myeloid Leukemia; Citric Acid Cycle; Glycolysis; PI3K/AKT/mTOR; Signaling Pathways

DOI:  https://doi.org/10.5812/ijpr-140507
Front Nutr. 2024 ;11 1266690

Ketogenic therapy towards precision medicine for brain diseases.

Yang Liu, Linlin Fan, Haoying Yang, Danli Wang, Runhan Liu, Tikun Shan, Xue Xia.

  Precision nutrition and nutrigenomics are emerging in the development of therapies for multiple diseases. The ketogenic diet (KD) is the most widely used clinical diet, providing high fat, low carbohydrate, and adequate protein. KD produces ketones and alters the metabolism of patients. Growing evidence suggests that KD has therapeutic effects in a wide range of neuronal diseases including epilepsy, neurodegeneration, cancer, and metabolic disorders. Although KD is considered to be a low-side-effect diet treatment, its therapeutic mechanism has not yet been fully elucidated. Also, its induced keto-response among different populations has not been elucidated. Understanding the ketone metabolism in health and disease is critical for the development of KD-associated therapeutics and synergistic therapy under any physiological background. Here, we review the current advances and known heterogeneity of the KD response and discuss the prospects for KD therapy from a precision nutrition perspective.

Keywords:  brain disease; ketogenic diet; neural disease; nutrigenomics; precision medicine

DOI:  https://doi.org/10.3389/fnut.2024.1266690
Biomed Pharmacother. 2024 Mar 02. pii: S0753-3322(24)00246-4. [Epub ahead of print]173 116362

Everolimus decreases [U-13C]glucose utilization by pyruvate carboxylase in breast cancer cells in vitro and in vivo.

Gerke Ariaans, Jiske F Tiersma, Bernardus Evers, Albert Gerding, Stijn J H Waaijer, Remco A Koster, Daan J Touw, Barbara M Bakker, Dirk-Jan Reijngoud, Steven de Jong, Mathilde Jalving.

  Reprogrammed metabolism is a hallmark of cancer, but notoriously difficult to target due to metabolic plasticity, especially in response to single metabolic interventions. Combining mTOR inhibitor everolimus and mitochondrial complex 1 inhibitor metformin results in metabolic synergy in in vitro models of triple-negative breast cancer. Here, we investigated whether the effect of this drug combination on tumor size is reflected in changes in tumor metabolism using [U-13C]glucose labeling in an MDA-MB-231 triple negative breast cancer xenograft model. The in vitro effects of everolimus and metformin treatment on oxidative phosphorylation and glycolysis reflected changes in 13C-labeling of metabolites in MDA-MB-231 cells. Treatment of MDA-MB-231 xenografts in SCID/Beige mice with everolimus resulted in slower tumor growth and reduced tumor size and tumor viability by 35%. Metformin treatment moderately inhibited tumor growth but did not enhance everolimus-induced effects. High serum levels of everolimus were reached, whereas levels of metformin were relatively low. Everolimus decreased TCA cycle metabolite labeling and inhibited pyruvate carboxylase activity. Metformin only caused a mild reduction in glycolytic metabolite labeling and did not affect pyruvate carboxylase activity or TCA cycle metabolite labeling. In conclusion, treatment with everolimus, but not metformin, decreased tumor size and viability. Furthermore, the efficacy of everolimus was reflected in reduced 13C-labeling of TCA cycle intermediates and reduced pyruvate carboxylase activity. By using in-depth analysis of drug-induced changes in glucose metabolism in combination with measurement of drug levels in tumor and plasma, effects of metabolically targeted drugs can be explained, and novel targets can be identified.

Keywords:  Breast cancer; Cancer metabolism; Everolimus; Metformin; [U-(13)C]glucose

DOI:  https://doi.org/10.1016/j.biopha.2024.116362
Magn Reson Med. 2024 Mar 05.

Current methods for hyperpolarized [1-13 C]pyruvate MRI human studies.

HP 13C MRI Consensus Group

  MRI with hyperpolarized (HP) 13 C agents, also known as HP 13 C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of HP agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13 C]pyruvate-by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13 C-pyruvate preparation; (2) MRI system setup and calibrations; (3) data acquisition and image reconstruction; and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the "HP 13 C MRI Consensus Group" as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods and Equipment study groups. It further aims to provide a comprehensive reference for future consensus, building as the field continues to advance human studies with this metabolic imaging modality.

Keywords:  carbon-13; dissolution dynamic nuclear polarization; hyperpolarized MRI; metabolic imaging; pyruvate

DOI:  https://doi.org/10.1002/mrm.29875
Nutrition. 2024 Feb 10. pii: S0899-9007(24)00044-3. [Epub ahead of print]122 112394

Postabsorptive and postprandial glucose and fat metabolism in postmenopausal women with breast cancer-Preliminary data after chemotherapy compared to healthy controls.

Kristian Buch-Larsen, Linn Gillberg, Haboon Ismail Ahmed, Simone Diedrichsen Marstrand, Michael Andersson, Gerrit van Hall, Charlotte Brøns, Peter Schwarz.

  BACKGROUND: Breast cancer survivors are a growing population due to improved treatment. It is known that postmenopausal women treated for breast cancer may experience weight gain and increased insulin resistance, but detailed knowledge on how chemotherapy impact metabolic and endocrine mechanisms remain unknown.OBJECTIVES: We performed a thorough, preliminary study to elucidate the differing mechanisms of postprandial absorption and metabolism in postmenopausal early breast cancer (EBC) patients treated with adjuvant chemotherapy compared to healthy controls. We hypothesize that chemotherapy has a negative impact on metabolism in EBC patients.
METHODS: We examined four postmenopausal women shortly after treatment with chemotherapy for EBC and four age-matched healthy women who served as controls using isotopic tracers during a mixed meal-test. Blood was sampled during the 240 min meal-test to examine postprandial absorption and endogenous synthesis of lipid and carbohydrate metabolites.
RESULTS: We found that insulin concentrations were numerically higher before the meal-test in the EBC patients compared to controls (76.3 pmol/L vs 37.0 pmol/L; P = 0.06). Glucose kinetics was increased postprandial (most pronounced at 30 min, 9.46 mmol/L vs 7.33 mmol/L; P = 0.51), with no difference between the groups regarding liver glucose output. Fatty acid kinetics showed a numeric increase in oleic acid rate of appearance in BC patients, but only during the first hour after the mixed meal. There was no significant difference in VLDL-TAG synthesis between the two groups.
CONCLUSIONS: This preliminary study is unique in using advanced tracer methods to investigate in vivo metabolism of EBC patients after chemotherapy although no statistical differences in glucose and fatty acid kinetics was seen compared to controls. However, during the first two postprandial hours, oral glucose and oleic acid appearance in the systematic circulation was elevated in the EBC patients. This could be due to changes in gastrointestinal uptake and further studies with altered set-up could provide valuable insights.

Keywords:  Breast cancer; Chylomicron; Fatty acids; Glucose; Meal test; Metabolism; VLDL-TAG

DOI:  https://doi.org/10.1016/j.nut.2024.112394
Autophagy. 2024 Mar 04. 1-15

Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells.

Sergio Díaz-Gago, Javier Vicente-Gutiérrez, Jose Manuel Ruiz-Rodríguez, Josep Calafell, Alicia Álvarez-Álvarez, Marina Lasa, Antonio Chiloeches, Pablo Baquero.

  BRAFV600E is the most prevalent mutation in thyroid cancer and correlates with poor prognosis and therapy resistance. Although selective inhibitors of BRAFV600E have been developed, more advanced tumors such as anaplastic thyroid carcinomas show a poor response in clinical trials. Therefore, the study of alternative survival mechanisms is needed. Since metabolic changes have been related to malignant progression, in this work we explore metabolic dependencies of thyroid tumor cells to exploit them therapeutically. Our results show that respiration of thyroid carcinoma cells is highly dependent on fatty acid oxidation and, in turn, fatty acid mitochondrial availability is regulated through macroautophagy/autophagy. Furthermore, we show that both lysosomal inhibition and the knockout of the essential autophagy gene, ATG7, lead to enhanced lipolysis; although this effect is not essential for survival of thyroid carcinoma cells. We also demonstrate that following inhibition of either autophagy or fatty acid oxidation, thyroid tumor cells compensate oxidative phosphorylation deficiency with an increase in glycolysis. In contrast to lipolysis induction, upon autophagy inhibition, glycolytic boost in autophagy-deficient cells is essential for survival and, importantly, correlates with a higher sensitivity to the BRAFV600E selective inhibitor, vemurafenib. In agreement, downregulation of the glycolytic pathway results in enhanced mitochondrial respiration and vemurafenib resistance. Our work provides new insights into the role of autophagy in thyroid cancer metabolism and supports mitochondrial targeting in combination with vemurafenib to eliminate BRAFV600E-positive thyroid carcinoma cells.Abbreviations: AMP: adenosine monophosphate; ATC: anaplastic thyroid carcinoma; ATG: autophagy related; ATP: adenosine triphosphate; BRAF: B-Raf proto-oncogene, serine/threonine kinase; Cas9: CRISPR-associated protein; CREB: cAMP responsive element binding protein; CRISPR: clustered regularly interspaced short palindromic repeats; 2DG: 2-deoxyglucose; FA: fatty acid; FAO: fatty acid oxidation; FASN: fatty acid synthase; FCCP: trifluoromethoxy carbonyl cyanide phenylhydrazone; LAMP1: lysosomal associated membrane protein 1; LIPE/HSL: lipase E, hormone sensitive type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PRKA/PKA: protein kinase cAMP-activated; PTC: papillary thyroid carcinoma; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1.

Keywords:  Cancer metabolism; fatty acid oxidation; glycolysis; oxidative phosphorylation; thyroid cancer; vemurafenib resistance

DOI:  https://doi.org/10.1080/15548627.2024.2312790
J Exp Clin Cancer Res. 2024 Mar 08. 43(1): 74

A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.

Bolin Wang, Jinli Pei, Shengnan Xu, Jie Liu, Jinming Yu.

  Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.

Keywords:  Cancer; Glutamine metabolism; Immune cells; Therapeutic strategies; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-024-02994-0
Front Pharmacol. 2024 ;15 1335785

Targeting SHMTs and MTHFDs in cancer: attractive opportunity for anti-tumor strategy.

Xue Zhang, Zhenhua Wang.

  One-carbon metabolism is a universal metabolic process that mediates the transfer of one-carbon units for purine and thymidine synthesis. One-carbon metabolism has been found to be dysregulated in various cancer types due to its role in production of purine and pyrimidine nucleotides, epigenetic program, and redox homeostasis. One-carbon metabolism is composed a network of one-carbon metabolic enzymes. Disturbing the expression and enzymatic activity of these one-carbon metabolic enzymes could lead to fluctuations of metabolites in the tumor microenvironment. Serine hydroxymethyltransferases (SHMTs) and methylenetetrahydrofolate dehydrogenases (MTHFDs) are gradually recognized as important one-carbon metabolic enzymes for regulating tumor initiation and development, representing potential therapeutic targets for anti-tumor strategies. In the review, we primarily focused on the role of SHMTs and MTHFDs in cancer. Several inhibitors targeting MTHFDs and SHMTs have exert its potential to decrease tumor burden and inhibit tumor proliferation, highlighting the potential of targeting one-carbon metabolic enzymes for anti-cancer strategies.

Keywords:  MTHFD family; metabolic enzyme; metabolism; one carbon metabolism; tumorigenesis

DOI:  https://doi.org/10.3389/fphar.2024.1335785
Biomicrofluidics. 2024 Mar;18(2): 024101

A miniaturized culture platform for control of the metabolic environment.

Marta K Orlowska, James R Krycer, Janice D Reid, Richard J Mills, Michael R Doran, James E Hudson.

The heart is a metabolic "omnivore" and adjusts its energy source depending on the circulating metabolites. Human cardiac organoids, a three-dimensional in vitro model of the heart wall, are a useful tool to study cardiac physiology and pathology. However, cardiac tissue naturally experiences shear stress and nutrient fluctuations via blood flow in vivo, whilst in vitro models are conventionally cultivated in a static medium. This necessitates the regular refreshing of culture media, which creates acute cellular disturbances and large metabolic fluxes. To culture human cardiac organoids in a more physiological manner, we have developed a perfused bioreactor for cultures in a 96-well plate format. The designed bioreactor is easy to fabricate using a common culture plate and a 3D printer. Its open system allows for the use of traditional molecular biology techniques, prevents flow blockage issues, and provides easy access for sampling and cell assays. We hypothesized that a perfused culture would create more stable environment improving cardiac function and maturation. We found that lactate is rapidly produced by human cardiac organoids, resulting in large fluctuations in this metabolite under static culture. Despite this, neither medium perfusion in bioreactor culture nor lactate supplementation improved cardiac function or maturation. In fact, RNA sequencing revealed little change across the transcriptome. This demonstrates that cardiac organoids are robust in response to fluctuating environmental conditions under normal physiological conditions. Together, we provide a framework for establishing an easily accessible perfusion system that can be adapted to a range of miniaturized cell culture systems.

DOI: https://doi.org/10.1063/5.0169143
Nat Chem Biol. 2024 Mar 06.

Mitochondrial ATP generation is more proteome efficient than glycolysis.

Yihui Shen, Hoang V Dinh, Edward R Cruz, Zihong Chen, Caroline R Bartman, Tianxia Xiao, Catherine M Call, Rolf-Peter Ryseck, Jimmy Pratas, Daniel Weilandt, Heide Baron, Arjuna Subramanian, Zia Fatma, Zong-Yen Wu, Sudharsan Dwaraknath, John I Hendry, Vinh G Tran, Lifeng Yang, Yasuo Yoshikuni, Huimin Zhao, Costas D Maranas, Martin Wühr, Joshua D Rabinowitz.

Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although respiration is more energy efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (that is, faster). Through quantitative flux analysis and proteomics, we find, however, that mitochondrial respiration is actually more proteome efficient than aerobic glycolysis. This is shown across yeast strains, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. We accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

DOI: https://doi.org/10.1038/s41589-024-01571-y
Nat Commun. 2024 Mar 02. 15(1): 1931

Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.

Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason.

Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.

DOI: https://doi.org/10.1038/s41467-024-46114-0
PLoS One. 2024 ;19(3): e0300150

Real-time resolution studies of the regulation of lactate production by hexokinases binding to mitochondria in single cells.

Scott John, Guillaume Calmettes, Shili Xu, Bernard Ribalet.

During hypoxia accumulation of lactate may be a key factor in acidosis-induced tissue damage. Binding of hexokinase (HK) to the outer membrane of mitochondria may have a protective effect under these conditions. We have investigated the regulation of lactate metabolism by hexokinases (HKs), using HEK293 cells in which the endogenous hexokinases have been knocked down to enable overexpression of wild type and mutant HKs. To assess the real-time changes in intracellular lactate levels the cells were also transfected with a lactate specific FRET probe. In the HKI/HKII double knockdown HEK cells, addition of extracellular pyruvate caused a large and sustained decrease in lactate. Upon inhibition of the mitochondrial electron transfer chain by NaCN this effect was reversed as a rapid increase in lactate developed which was followed by a slow and sustained increase in the continued presence of the inhibitor. Incubation of the HKI/HKII double knockdown HEK cells with the inhibitor of the malic enzyme, ME1*, blocked the delayed accumulation of lactate evoked by NaCN. With replacement by overexpression of HKI or HKII the accumulation of intracellular lactate evoked by NaCN was prevented. Blockage of the pentose phosphate pathway with the inhibitor 6-aminonicotinamide (6-AN) abolished the protective effect of HK expression, with NaCN causing again a sustained increase in lactate. The effect of HK was dependent on HK's catalytic activity and interaction with the mitochondrial outer membrane (MOM). Based on these data we propose that transformation of glucose into G6P by HK activates the pentose phosphate pathway which increases the production of NADPH, which then blocks the activity of the malic enzyme to transform malate into pyruvate and lactate.

DOI: https://doi.org/10.1371/journal.pone.0300150
J Leukoc Biol. 2024 Mar 07. pii: qiae057. [Epub ahead of print]

Not just sugar: Metabolic control of neutrophil development and effector functions.

Paul Ettel, Thomas Weichhart.

  The mammalian immune system is constantly surveying our tissues to clear pathogens and maintain tissue homeostasis. In order to fulfill these tasks, immune cells take up nutrients to supply energy for survival and for directly regulating effector functions via their cellular metabolism; a process now known as immunometabolism. Neutrophilic granulocytes, the most abundant leukocytes in the human body, have a short half-life and are permanently needed in the defense against pathogens. According to a long-standing view, neutrophils were thought to primarily fuel their metabolic demands via glycolysis. Yet, this view has been challenged as other metabolic pathways recently emerged to contribute to neutrophil homeostasis and effector functions. In particular during neutrophilic development, the pentose phosphate pathway, glycogen synthesis, oxidative phosphorylation, and fatty acid oxidation crucially promote neutrophil maturation. At steady state, both glucose and lipid metabolism sustain neutrophil survival and maintain the intracellular redox balance. This review aims to comprehensively discuss how neutrophilic metabolism adapts during development, which metabolic pathways fuel their functionality and how these processes are reconfigured in case of various diseases. We provide several examples of hereditary diseases, where mutations in metabolic enzymes validate their critical role for neutrophil function.

Keywords:  immunometabolism; innate immunity; metabolism; neutrophil

DOI:  https://doi.org/10.1093/jleuko/qiae057
Nat Commun. 2024 Mar 05. 15(1): 1987

Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.

Fatima Khan, Yiyun Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek A Wainwright, Kathleen McCortney, Leah K Billingham, Jason Miska, Craig Horbinski, Maciej S Lesniak, Peiwen Chen.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.

DOI: https://doi.org/10.1038/s41467-024-46193-z
Adv Clin Exp Med. 2024 Mar 01.

Mechanisms of resistance to venetoclax in hematologic malignancies.

Klaudia Zielonka, Krzysztof Jamroziak.

  Venetoclax, a BH3 mimetic, is a novel targeted anti-cancer drug with a unique mechanism of action leading to the execution of apoptosis through inhibition of the Bcl-2 protein. The development of venetoclax has revolutionized the treatment paradigm of several hematologic malignancies, including treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML) in unfit patients. However, despite the high effectiveness of venetoclax in these diseases, some patients, as in the case with other targeted therapies, develop primary or secondary resistance to the drug. Various mechanisms contributing to the resistance to venetoclax have been elucidated, including selection of mutations in the BCL-2 binding groove which decrease affinity to venetoclax, or compensatory overexpression of anti-apoptotic proteins such as MCL-1. Moreover, alterations in cell metabolism and signaling pathways like MAPK or ERK activation have also been reported, suggesting the resistance to venetoclax is highly complex and involves multiple pathways. This review aimed to describe the mechanisms of resistance to venetoclax in AML, CLL, multiple myeloma, and other hematologic malignancies, as well as to propose a perspective to circumvent it.

Keywords:  acute myeloid leukemia; apoptosis; chronic lymphocytic leukemia; resistance; venetoclax

DOI:  https://doi.org/10.17219/acem/181145
Cell Metab. 2024 Mar 01. pii: S1550-4131(24)00050-0. [Epub ahead of print]

Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.

Stanislaw Deja, Justin A Fletcher, Chai-Wan Kim, Blanka Kucejova, Xiaorong Fu, Monika Mizerska, Morgan Villegas, Natalia Pudelko-Malik, Nicholas Browder, Melissa Inigo-Vollmer, Cameron J Menezes, Prashant Mishra, Eric D Berglund, Jeffrey D Browning, John P Thyfault, Jamey D Young, Jay D Horton, Shawn C Burgess.

  Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition of ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic inhibition of ACC increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, and gluconeogenesis by activating hepatic CPT-1 and pyruvate carboxylase flux in the fed state. Fasting should have marginalized the role of ACC, but LDKO mice maintained elevated TCA cycle intermediates and preserved glycemia during fasting. These effects were accompanied by a compensatory induction of proteolysis and increased amino acid supply for gluconeogenesis, which was offset by increased protein synthesis during feeding. Such adaptations may be related to Nrf2 activity, which was induced by ACC inhibition and correlated with fasting amino acids. The findings reveal unexpected roles for malonyl-CoA synthesis in liver and provide insight into the broader effects of pharmacologic ACC inhibition.

Keywords:  Nrf2; TCA cycle; acetyl-CoA carboxylase; anaplerosis; autophagy; gluconeogenesis; lipogenesis; malonyl-CoA; protein synthesis; proteolysis

DOI:  https://doi.org/10.1016/j.cmet.2024.02.004
Biophys J. 2024 Mar 06. pii: S0006-3495(24)00176-0. [Epub ahead of print]

How and When to Measure Mitochondrial Inner Membrane Potentials.

Alicia J Kowaltowski, Fernando Abdulkader.

The scientific literature on mitochondria has increased significantly over the years, due to findings that these organelles have widespread roles in the onset and progression of pathological conditions such as metabolic disorders, neurodegenerative and cardiovascular diseases, inflammation, and cancer. Researchers have extensively explored how mitochondrial properties and functions are modified in different models, often using fluorescent inner mitochondrial membrane potential (ΔΨm) probes to assess functional mitochondrial aspects such as protonmotive force and oxidative phosphorylation. This review provides an overview of existing techniques to measure ΔpH and ΔΨm, highlighting their advantages, limitations, and applications. It discusses drawbacks of ΔΨm probes, especially when used without calibration, and conditions where alternative methods should replace ΔΨm measurements for the benefit of the specific scientific objectives entailed. Studies investigating mitochondria and their vast biological roles would be significantly advanced by the understanding of the correct applications as well as limitations of protonmotive force measurements and use of fluorescent ΔΨm probes, adopting more precise, artifact-free, sensitive, and quantitative measurements of mitochondrial functionality.

DOI: https://doi.org/10.1016/j.bpj.2024.03.011
Front Oncol. 2024 ;14 1286896

Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.

Tushar H More, Karsten Hiller, Martin Seifert, Thomas Illig, Rudi Schmidt, Raphael Gronauer, Thomas von Hahn, Hauke Weilert, Axel Stang.

  Background: Cachexia is a body wasting syndrome that significantly affects well-being and prognosis of cancer patients, without effective treatment. Serum metabolites take part in pathophysiological processes of cancer cachexia, but apart from altered levels of select serum metabolites, little is known on the global changes of the overall serum metabolome, which represents a functional readout of the whole-body metabolic state. Here, we aimed to comprehensively characterize serum metabolite alterations and analyze associated pathways in cachectic cancer patients to gain new insights that could help instruct strategies for novel interventions of greater clinical benefit.Methods: Serum was sampled from 120 metastatic cancer patients (stage UICC IV). Patients were grouped as cachectic or non-cachectic according to the criteria for cancer cachexia agreed upon international consensus (main criterium: weight loss adjusted to body mass index). Samples were pooled by cachexia phenotype and assayed using non-targeted gas chromatography-mass spectrometry (GC-MS). Normalized metabolite levels were compared using t-test (p < 0.05, adjusted for false discovery rate) and partial least squares discriminant analysis (PLS-DA). Machine-learning models were applied to identify metabolite signatures for separating cachexia states. Significant metabolites underwent MetaboAnalyst 5.0 pathway analysis.
Results: Comparative analyses included 78 cachectic and 42 non-cachectic patients. Cachectic patients exhibited 19 annotable, significantly elevated (including glucose and fructose) or decreased (mostly amino acids) metabolites associating with aminoacyl-tRNA, glutathione and amino acid metabolism pathways. PLS-DA showed distinct clusters (accuracy: 85.6%), and machine-learning models identified metabolic signatures for separating cachectic states (accuracy: 83.2%; area under ROC: 88.0%). We newly identified altered blood levels of erythronic acid and glucuronic acid in human cancer cachexia, potentially linked to pentose-phosphate and detoxification pathways.
Conclusion: We found both known and yet unknown serum metabolite and metabolic pathway alterations in cachectic cancer patients that collectively support a whole-body metabolic state with impaired detoxification capability, altered glucose and fructose metabolism, and substrate supply for increased and/or distinct metabolic needs of cachexia-associated tumors. These findings together imply vulnerabilities, dependencies and targets for novel interventions that have potential to make a significant impact on future research in an important field of cancer patient care.

Keywords:  GC-MS metabolomics; body metabolism; cancer cachexia; erythronic acid; glucuronic acid; metabolic pathways; serum metabolites

DOI:  https://doi.org/10.3389/fonc.2024.1286896
Front Oncol. 2024 ;14 1367393

Literature review and expert opinion on the treatment of high-risk acute myeloid leukemia in patients who are eligible for intensive chemotherapy.

Raffaele Palmieri, Atto Billio, Felicetto Ferrara, Sara Galimberti, Roberto M Lemoli, Elisabetta Todisco, Federico Moretti, Adriano Venditti.

  In patients with Acute Myeloid Leukemia (AML), the assessment of disease risk plays a central role in the era of personalized medicine. Indeed, integrating baseline clinical and biological features on a case-by-case basis is not only essential to select which treatment would likely result in a higher probability of achieving complete remission, but also to dynamically customize any subsequent therapeutic intervention. For young high-risk patients with low comorbidities burden and in good general conditions (also called "fit" patients), intensive chemotherapy followed by allogeneic stem cell transplantation still represents the backbone of any therapeutic program. However, with the approval of novel promising agents in both the induction/consolidation and the maintenance setting, the algorithms for the management of AML patients considered eligible for intensive chemotherapy are in constant evolution. In this view, we selected burning issues regarding the identification and management of high-risk AML, aiming to provide practical advice to facilitate their daily clinical management in patients considered eligible for intensive chemotherapy.

Keywords:  acute leukemia; acute myeloid leukemia; clinical prognosticators; disease biology; fitness

DOI:  https://doi.org/10.3389/fonc.2024.1367393
Food Sci Nutr. 2024 Mar;12(3): 1444-1464

The impact of ketogenic diet on some metabolic and non-metabolic diseases: Evidence from human and animal model experiments.

Yaseen Galali, Salih M S Zebari, Ahmed Aj Jabbar, Holem Hashm Balaky, Bashdar Abuzed Sadee, Hamed Hassanzadeh.

  The ketogenic diet (KD) is recognized as minimum carbohydrate and maximum fat intakes, which leads to ketosis stimulation, a state that is thought to metabolize fat more than carbohydrates for energy supply. KD has gained more interest in recent years and is for many purposes, including weight loss and managing serious diseases like type 2 diabetes. On the other hand, many believe that KD has safety issues and are uncertain about the health drawbacks. Thus, the outcomes of the effect of KD on metabolic and non-metabolic disease remain disputable. The current narrative review aims to evaluate the effect of KD on several diseases concerning the human health. To our best knowledge, the first report aims to investigate the efficacy of KD on multiple human health issues including type 2 diabetes and weight loss, cardiovascular disease, kidney failure and hypertension, non-alcoholic fatty liver, mental problem, oral health, libido, and osteoporosis. The literature searches were performed in Databases, PubMed, Scopus, and web of Science looking for both animal and human model designs. The results heterogeneity seems to be explained by differences in diet composition and duration. Also, the available findings may show that proper control of carbohydrates, a significant reduction in glycemic control and glycated hemoglobin, and weight loss by KD can be an approach to improve diabetes and obesity, hypertension, non-alcoholic fatty liver, PCOS, libido, oral health, and mental problem if isocaloric is considered. However, for some other diseases like cardiovascular disease and osteoporosis, more robust data are needed. Therefore, there is robust data to support the notion that KD can be effective for some metabolic and non-metabolic diseases but not for all of them. So they have to be followed cautiously and under the supervision of health professionals.

Keywords:  cardiovascular disease; diabetes and weight loss; keto diet; metabolic and non‐metabolic diseases

DOI:  https://doi.org/10.1002/fsn3.3873
Cancer Med. 2024 Feb;13(4): e7073

Perceiving a need for dietary change in adults living with and beyond cancer: A cross-sectional study.

Susan Smith, Abi Fisher, Phillippa J Lally, Helen A Croker, Anna Roberts, Rana E Conway, Rebecca J Beeken.

  BACKGROUND: Many people living with and beyond cancer (LWBC) do not meet dietary recommendations. To implement a healthier diet, people LWBC must perceive a need to improve their diet.METHODS: Participants included people diagnosed with breast, prostate or colorectal cancer in the UK. Two binary logistic regression models were conducted with perceived need for dietary change as the outcome (need to improve vs. no need). Predictor variables included demographic and clinical characteristics, receipt of dietary advice, and either body mass index (BMI) or adherence to seven relevant World Cancer Research Fund (WCRF) dietary recommendations.
RESULTS: The sample included 5835 responses. Only 31% perceived a need to improve their diet. Being younger (odds ratio [OR] 0.95, 95% confidence interval [CI] = 94-0.95), female (OR = 1.33, 95% CI = 1.15-1.53), not of white ethnicity (OR = 1.8, 95% CI = 1.48-2.27), not married/cohabiting (OR = 1.32, 95% CI = 1.16-1.52) and having received dietary advice (OR = 1.36, 95% CI = 1.43-1.86) was associated with an increased odds of perceiving a need to improve diet. This association was also seen for participants with two or more comorbidities (OR = 1.31, 95% CI = 1.09-1.57), those not meeting the recommendations for fruit and vegetables (OR = 0.47, 95% CI = 0.41-0.55), fat (OR = 0.67, 95% CI = 0.58-0.77), and sugar (OR = 0.86, 95% CI = 0.75-0.98) in the dietary components model and those who had a higher BMI (OR = 1.53, 95% CI = 1.32-1.77) in the BMI model.
CONCLUSIONS: Most of this sample of people LWBC did not perceive a need to improve their diet. More research is needed to understand the reasons for this and to target these reasons in dietary interventions.

Keywords:  cancer survivors; diet; diet quality; energy intake; healthy diet; nutrition surveys

DOI:  https://doi.org/10.1002/cam4.7073
Eur J Clin Nutr. 2024 Mar 08.

Mediterranean-style dietary interventions in adults with cancer: a systematic review of the methodological approaches, feasibility, and preliminary efficacy.

Aoife McHugh, Ellie O'Connell, Bridie Gurd, Paige Rae, Elena S George, Amber S Kleckner, Brenton J Baguley.

BACKGROUND: Cancer and its treatments can lead to excess body fat, decreases in lean mass, cardiotoxicity, and other side effects. The Mediterranean diet (MED-diet) has the potential to improve clinical and supportive care outcomes. The aim of this systematic review was to evaluate the feasibility, safety, and efficacy of the MED-diet on health outcomes in adults with cancer.METHODS: Three databases were searched from inception to February 2023. Eligible studies included randomised controlled trials testing a MED-diet intervention among adults with cancer. Within- and between-group differences for adherence, dietary intake and health outcomes were extracted.
RESULTS: Fifteen studies describing fourteen interventions were included, and there were considerable differences in study design and implementation of the MED-diet. Studies were predominately in women with a history of breast cancer. The MED-diet was safe with no adverse events reported, and feasible with high adherence and/or increases in MED-diet-compliant foods. The MED-diet when applied with an energy restriction below estimated requirements for weight loss demonstrated reductions in body weight (range: -3.9 kg to -0.7 kg). Interventions that showed significant reductions in body weight also improved quality of life. There is limited evidence to evaluating the MED-diet on cardiovascular and inflammatory markers, and heterogenous MED-diet prescriptions impede definitive conclusions on these health outcomes.
CONCLUSION: The MED-diet was feasible and safe for adults with cancer. There were reported benefits for weight loss following a MED-diet when an energy restriction was applied, however further evaluation to determine the effects on cardiometabolic biomarkers and other outcomes are required.

DOI: https://doi.org/10.1038/s41430-024-01426-8
Nat Cell Biol. 2024 Mar 07.

Lipid droplets and cellular lipid flux.

Alyssa J Mathiowetz, James A Olzmann.

Lipid droplets are dynamic organelles that store neutral lipids, serve the metabolic needs of cells, and sequester lipids to prevent lipotoxicity and membrane damage. Here we review the current understanding of the mechanisms of lipid droplet biogenesis and turnover, the transfer of lipids and metabolites at membrane contact sites, and the role of lipid droplets in regulating fatty acid flux in lipotoxicity and cell death.

DOI: https://doi.org/10.1038/s41556-024-01364-4
ESMO Open. 2024 Mar 04. pii: S2059-7029(24)00009-7. [Epub ahead of print]9(3): 102241

Body mass index, weight change, and cancer prognosis: a meta-analysis and systematic review of 73 cohort studies.

H Wen, G Deng, X Shi, Z Liu, A Lin, Q Cheng, J Zhang, P Luo.

  BACKGROUND: Identifying the association between body mass index (BMI) or weight change and cancer prognosis is essential for the development of effective cancer treatments. We aimed to assess the strength and validity of the evidence of the association between BMI or weight change and cancer prognosis by a systematic evaluation and meta-analysis of relevant cohort studies.METHODS: We systematically searched the PubMed, Web of Science, EconLit, Embase, Food Sciences and Technology Abstracts, PsycINFO, and Cochrane databases for literature published up to July 2023. Inclusion criteria were cohort studies with BMI or weight change as an exposure factor, cancer as a diagnostic outcome, and data type as an unadjusted hazard ratio (HR) or headcount ratio. Random- or fixed-effects models were used to calculate the pooled HR along with the 95% confidence interval (CI).
RESULTS: Seventy-three cohort studies were included in the meta-analysis. Compared with normal weight, overweight or obesity was a risk factor for overall survival (OS) in patients with breast cancer (HR 1.37, 95% CI 1.22-1.53; P < 0.0001), while obesity was a protective factor for OS in patients with gastrointestinal tumors (HR 0.67, 95% CI 0.56-0.80; P < 0.0001) and lung cancer (HR 0.67, 95% CI 0.48-0.92; P = 0.01) compared with patients without obesity. Compared with normal weight, underweight was a risk factor for OS in patients with breast cancer (HR 1.15, 95% CI 0.98-1.35; P = 0.08), gastrointestinal tumors (HR 1.54, 95% CI 1.32-1.80; P < 0.0001), and lung cancer (HR 1.28, 95% CI 1.22-1.35; P < 0.0001). Compared with nonweight change, weight loss was a risk factor for OS in patients with gastrointestinal cancer.
CONCLUSIONS: Based on the results of the meta-analysis, we concluded that BMI, weight change, and tumor prognosis were significantly correlated. These findings may provide a more reliable argument for the development of more effective oncology treatment protocols.

Keywords:  body mass index (BMI); cancer; meta-analysis; obesity; survival; weight change

DOI:  https://doi.org/10.1016/j.esmoop.2024.102241
Arch Microbiol. 2024 Mar 04. 206(4): 137

Butyrate's (a short-chain fatty acid) microbial synthesis, absorption, and preventive roles against colorectal and lung cancer.

Md Rezaul Karim, Safia Iqbal, Shahnawaz Mohammad, Md Niaj Morshed, Md Anwarul Haque, Ramya Mathiyalagan, Deok Chun Yang, Yeon Ju Kim, Joong Hyun Song, Dong Uk Yang.

  Butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, is a source of energy for colonocytes. Butyrate is essential for improving gastrointestinal (GI) health since it helps colonocyte function, reduces inflammation, preserves the gut barrier, and fosters a balanced microbiome. Human colonic butyrate producers are Gram-positive firmicutes, which are phylogenetically varied. The two most prevalent subgroups are associated with Eubacterium rectale/Roseburia spp. and Faecalibacterium prausnitzii. Now, the mechanism for the production of butyrate from microbes is a very vital topic to know. In the present study, we discuss the genes encoding the core of the butyrate synthesis pathway and also discuss the butyryl-CoA:acetate CoA-transferase, instead of butyrate kinase, which usually appears to be the enzyme that completes the process. Recently, butyrate-producing microbes have been genetically modified by researchers to increase butyrate synthesis from microbes. The activity of butyrate as a histone deacetylase inhibitor (HDACi) has led to several clinical trials to assess its effectiveness as a potential cancer treatment. Among various significant roles, butyrate is the main energy source for intestinal epithelial cells, which helps maintain colonic homeostasis. Moreover, people with non-small-cell lung cancer (NSCLC) have distinct gut microbiota from healthy adults and frequently have dysbiosis of the butyrate-producing bacteria in their guts. So, with an emphasis on colon and lung cancer, this review also discusses how the microbiome is crucial in preventing the progression of certain cancers through butyrate production. Further studies should be performed to investigate the underlying mechanisms of how these specific butyrate-producing bacteria can control both colon and lung cancer progression and prognosis.

Keywords:  Butyrate; Colon cancer; Histone deacetylase inhibitor (HDACi); Lung cancer; Short-chain fatty acid (SCFA)

DOI:  https://doi.org/10.1007/s00203-024-03834-7
Cell Rep. 2024 Mar 05. pii: S2211-1247(24)00240-7. [Epub ahead of print]43(3): 113912

Cellular senescence is associated with the spatial evolution toward a higher metastatic phenotype in colorectal cancer.

Soon Sang Park, Young-Kyoung Lee, Yong Won Choi, Su Bin Lim, So Hyun Park, Han Ki Kim, Jun Sang Shin, Young Hwa Kim, Dong Hyun Lee, Jang-Hee Kim, Tae Jun Park.

  In this study, we explore the dynamic process of colorectal cancer progression, emphasizing the evolution toward a more metastatic phenotype. The term "evolution" as used in this study specifically denotes the phenotypic transition toward a higher metastatic potency from well-formed glandular structures to collective invasion, ultimately resulting in the development of cancer cell buddings at the invasive front. Our findings highlight the spatial correlation of this evolution with tumor cell senescence, revealing distinct types of senescent tumor cells (types I and II) that play different roles in the overall cancer progression. Type I senescent tumor cells (p16INK4A+/CXCL12+/LAMC2-/MMP7-) are identified in the collective invasion region, whereas type II senescent tumor cells (p16INK4A+/CXCL12+/LAMC2+/MMP7+), representing the final evolved form, are prominently located in the partial-EMT region. Importantly, type II senescent tumor cells associate with local invasion and lymph node metastasis in colorectal cancer, potentially affecting patient prognosis.

Keywords:  CP: Cancer; LAMC2; MMP7; cancer buddings; cancer evolution; collective invasion; colorectal cancer; lymph node metastasis; senescent tumor cells; spatial evolution; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2024.113912