bims-medica 2024-11-24 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–11–24
thirty-six papers selected by
Brett Chrest, Wake Forest University

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
The combined treatment with ketogenic diet and metformin slows tumor growth in two mouse models of triple negative breast cancer.
Textbook oxidative phosphorylation needs to be rewritten.
DNMT3AR882H Is Not Required for Disease Maintenance in Primary Human AML, but Is Associated With Increased Leukemia Stem Cell Frequency.
Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma.
Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility.
Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
Ketogenic Food Ameliorates Activity-Based Anorexia of Adult Female Mice.
Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.
BCL-2 inhibition in acute myeloid leukemia: resistance and combinations.
Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.
The influence of endothelial metabolic reprogramming on the tumor microenvironment.
Systemic and transcriptional response to intermittent fasting and fasting-mimicking diet in mice.
Differential Effects of Confinement on the Dynamics of Normal and Tumor-Derived Pancreatic Ductal Organoids.
ATP Restoration by ATP-Deprived Cultured Primary Astrocytes.
Obesity predisposes to specific cancer driver mutations.
Glycemic load impacts the response of acquired resistance in breast cancer cells to chemotherapeutic drugs in vitro.
Diminished lactate utilization in LDHB-deficient neurons leads to impaired long-term memory retention.
The impact of diet induced obesity on 5 fluorouracil-induced tumor and liver immune cell cytotoxicity.
The association between non- and pro-healthy diet indices and the risk of colorectal cancer: a case-control study.
Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting.
What have we learned about TP53-mutated acute myeloid leukemia?
Global patterns of leukemia by subtype, age, and sex in 185 countries in 2022.
Effectiveness of resistance training in preventing sarcopenia among breast cancer patients undergoing chemotherapy: A systematic review and meta-analysis.
High-iron diet damages brown adipose tissue mitochondria and exacerbates metabolic hazards of a high-fat diet.
Research advances in branched-chain amino acid metabolism in tumors.
Proteogenomic profiling of acute myeloid leukemia to identify therapeutic targets.
Plasma metabolite profiles related to dietary patterns: exploring the association with colorectal tumor risk.
Association of low-carbohydrate diet score and carbohydrate quality index with colorectal cancer risk: a large-scale case-control study.
Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.
The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration.
A novel approach to regulate glucose uptake in an anaplastic thyroid cancer cell line.
Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.
Hypoalbuminemia and Nutritional Status in Children with Cancer.
Development of fluorescence lifetime biosensors for ATP, cAMP, citrate, and glucose using the mTurquoise2-based platform.
DNA methylation stochasticity is linked to transcriptional variability and identifies convergent epigenetic disruption across genetically-defined subtypes of AML.

bioRxiv. 2024 Nov 03. pii: 2024.10.31.621317. [Epub ahead of print]

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.

Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Althea Waldhart, Kelly H Sokol, Cameron J Lee, Samuel R Daniels, Joseph Longo, Amy Johnson, Ryan D Sheldon, Russell G Jones, Evan C Lien.

Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.

DOI: https://doi.org/10.1101/2024.10.31.621317
Transl Med Commun. 2024 ;pii: 21. [Epub ahead of print]9(1):

The combined treatment with ketogenic diet and metformin slows tumor growth in two mouse models of triple negative breast cancer.

Karen Schmidt, Amber Thatcher, Albert Grobe, Pamela Broussard, Linda Hicks, Haiwei Gu, Lesley G Ellies, Dorothy D Sears, Leonid Kalachev, Eugene Kroll.

   Background: Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions.
Methods: To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a mild reduction in systemic glucose by controlling both dietary carbohydrates with a ketogenic diet and endogenous glucose production by using metformin on two mouse models of triple-negative breast cancer (TNBC).
Results: Here, we showed that animals with TNBC treated with the combination regimen of ketogenic diet and metformin (a) had their tumor burden lowered by two-thirds, (b) displayed 38% slower tumor growth, and (c) showed 36% longer latency, compared to the animals treated with a ketogenic diet or metformin alone. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse TNBC models by 31 days, approximately equivalent to 3 years of life extension in human terms.
Conclusion: This preclinical study demonstrates that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types that can augment existing treatment options to improve patient outcomes.

Keywords:  Glycolytic tumor; Hypoxic tumor; Ketogenic diet; Metformin; Systemic glucose limitation

DOI:  https://doi.org/10.1186/s41231-024-00178-8
Trends Biochem Sci. 2024 Nov 21. pii: S0968-0004(24)00254-8. [Epub ahead of print]

Textbook oxidative phosphorylation needs to be rewritten.

Alicia J Kowaltowski, Fernando Abdulkader.

  Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.

Keywords:  complex I; ion transport; mitochondria; oxidative phosphorylation; sodium–proton exchange

DOI:  https://doi.org/10.1016/j.tibs.2024.11.002
bioRxiv. 2024 Oct 29. pii: 2024.10.26.620318. [Epub ahead of print]

DNMT3AR882H Is Not Required for Disease Maintenance in Primary Human AML, but Is Associated With Increased Leukemia Stem Cell Frequency.

Thomas Koehnke, Daiki Karigane, Eleanor Hilgart, Amy C Fan, Kensuke Kayamori, Masashi Miyauchi, Cailin T Collins, Fabian P Suchy, Athreya Rangavajhula, Yang Feng, Yusuke Nakauchi, Eduardo Martinez-Montes, Jonas Fowler, Kyle M Loh, Hiromitsu Nakauchi, Michael A Koldobskiy, Andrew P Feinberg, Ravindra Majeti.

Genetic mutations are being thoroughly mapped in human cancers, yet a fundamental question in cancer biology is whether such mutations are functionally required for cancer initiation, maintenance of established cancer, or both. Here, we study this question in the context of human acute myeloid leukemia (AML), where DNMT3AR882 missense mutations often arise early, in pre-leukemic clonal hematopoiesis, and corrupt the DNA methylation landscape to initiate leukemia. We developed CRISPR-based methods to directly correct DNMT3AR882 mutations in leukemic cells obtained from patients. Surprisingly, DNMT3AR882 mutations were largely dispensable for disease maintenance. Replacing DNMT3AR882 mutants with wild-type DNMT3A did not impair the ability of AML cells to engraft in vivo, and minimally altered DNA methylation. Taken together, DNMT3AR882 mutations are initially necessary for AML initiation, but are largely dispensable for disease maintenance. The notion that initiating oncogenes differ from those that maintain cancer has important implications for cancer evolution and therapy.

DOI: https://doi.org/10.1101/2024.10.26.620318
Neuro Oncol. 2024 Nov 22. pii: noae255. [Epub ahead of print]

Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma.

Han Shen, Faiqa Mudassar, Shiyong Ma, Xingyu Wang, Sandy Nguyen, Neha Bal, Quy-Susan Huynh, Dongwei Wang, Cecilia Chang, Prunella Ing, Winny Varikatt, Joey Lai, Brian Gloss, Jeff Holst, Geraldine M O'Neill, Harriet Gee, Kristina M Cook, Eric Hau.

   BACKGROUND: Diffuse Intrinsic Pontine Gliomas (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are brain tumors that primarily affect children. Radiotherapy is the standard of care but only provides temporary symptomatic relief due to radioresistance. While hypoxia is a major driver of radioresistance in other tumors, there is no definitive evidence that DIPGs are hypoxic. DIPGs often contain histone mutations, which alter tumor metabolism and are also associated with radioresistance. Our objective was to identify the metabolic profiles of DIPG cells, detect hypoxia signatures, and uncover metabolism-linked mechanisms of radioresistance to improve tumor radiosensitivity.
METHOD: Using DIPG models combined with clinical datasets, we examined mitochondrial metabolism and signatures of hypoxia. We explored DIPG reliance on mitochondrial metabolism using extracellular flux assays and targeted metabolomics. In vitro and in vivo models were used to explore the mechanisms of targeting mitochondrial bioenergetics and hypoxia for radiosensitization. Treatment-induced transcriptomics and metabolomics were also investigated.
RESULTS: Comprehensive analyses of DIPG cells show signatures of enhanced oxidative phosphorylation (OXPHOS). We also identified increased expression of specific OXPHOS related genes and signatures of hypoxia gene expression in datasets obtained from DIPG patients. We found the presence of hypoxia in orthotopic mouse models bearing DIPG tumors. These findings enabled us to develop a proof-of-concept treatment strategy to enhance radiosensitivity of DIPGs in vitro and in animal models.
CONCLUSION: DIPG cells rely on mitochondrial metabolism for growth, and targeting mitochondria disrupts bioenergetics, alleviates hypoxia, and enhances radiosensitivity. These findings warrant further exploration of OXPHOS inhibition as a radiosensitizing strategy for DIPG treatment.

Keywords:  diffuse intrinsic pontine gliomas; hypoxia; mitochondria; radiotherapy

DOI:  https://doi.org/10.1093/neuonc/noae255
Free Radic Biol Med. 2024 Nov 16. pii: S0891-5849(24)01018-9. [Epub ahead of print]226 237-250

Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility.

Ethan L Ostrom, Rudy Stuppard, Aurora Mattson-Hughes, David J Marcinek.

   INTRODUCTION: Skeletal muscle mitochondrial dysfunction is a key characteristic of aging muscle and contributes to age related diseases such as sarcopenia, frailty, and type 2 diabetes. Mitochondrial oxidative stress has been implicated as a driving factor in these age-related diseases, however whether it is a cause, or a consequence of mitochondrial dysfunction remains to be determined. The development of flexible genetic models is an important tool to test the mechanistic role of mitochondrial oxidative stress on skeletal muscle metabolic dysfunction. We characterize a new model of inducible and reversible mitochondrial redox stress using a tetracycline controlled skeletal muscle specific short hairpin RNA targeted to superoxide dismutase 2 (iSOD2).
METHODS: iSOD2 KD and control (CON) animals were administered doxycycline for 3- or 12- weeks and followed for up to 24 weeks and mitochondrial respiration and muscle contraction were measured to define the time course of SOD2 KD and muscle functional changes and recovery.
RESULTS: Maximum knockdown of SOD2 protein occurred by 6 weeks and recovered by 24 weeks after DOX treatment. Mitochondrial aconitase activity and maximum mitochondrial respiration declined in KD muscle by 12 weeks and recovered by 24 weeks. There were no significant differences in antioxidant or mitochondrial biogenesis genes between groups. Twelve-week KD showed a small, but significant decrease in muscle fatigue resistance. The primary phenotype was reduced metabolic flexibility characterized by impaired pyruvate driven respiration when other substrates are present. The pyruvate dehydrogenase kinase inhibitor dichloroacetate partially restored pyruvate driven respiration, while the thiol reductant DTT did not.
CONCLUSION: We use a model of inducible and reversible skeletal muscle SOD2 knockdown to demonstrate that elevated matrix superoxide reversibly impairs mitochondrial substrate flexibility characterized by impaired pyruvate oxidation. Despite the bioenergetic effect, the limited change in gene expression suggests that the elevated redox stress in this model is confined to the mitochondrial matrix.

Keywords:  Inducible SOD2 knockdown; Metabolic inflexibility; Mitochondrial oxidative stress; Mitochondrial respiration; Pyruvate oxidation; Skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.310
J Biol Chem. 2024 Nov 15. pii: S0021-9258(24)02506-7. [Epub ahead of print] 108004

Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.

Courtney R Green, Lynn M Alaeddine, Karl A Wessendorf-Rodriguez, Rory Turner, Merve Elmastas, Justin D Hover, Anne N Murphy, Mikael Ryden, Niklas Mejhert, Christian M Metallo, Martina Wallace.

  Dysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis are increased to compensate for loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion, however these cells did not upregulate pyruvate utilisation and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells, and that both metabolic and regulatory cross-talk exists between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.

Keywords:  adipogenesis; adipose; branched chain amino acids; glycolysis; metabolic flux

DOI:  https://doi.org/10.1016/j.jbc.2024.108004
Int J Eat Disord. 2024 Nov 16.

Ketogenic Food Ameliorates Activity-Based Anorexia of Adult Female Mice.

Yiru Dong, Yuki Lin, Latika Khatri, Moses Chao, Chiye Aoki.

   OBJECTIVE: Genome-wide association studies implicate metabo-psychiatric origins for anorexia nervosa (AN). There are two case reports totaling six adult females who experienced complete remission of AN following a treatment comprised of ketogenic diet (targeting metabolism) with ketamine infusions (targeting psychiatric origins), but no study has determined the efficacy of ketogenic diet, alone. We addressed this gap in knowledge, with exploration of potential molecular mechanisms, using an animal model.
METHOD: Adult C57BL6 female mice underwent 2 or 3 cycles of activity-based anorexia (ABA1, ABA2, ABA3), an animal model of AN relapse, in which AN-like maladaptive behaviors of hyperactivity and voluntary food restriction are elicited when wheel access is combined with food restriction. ABA was categorized as severe, based on weight loss ≥ 20%, food restriction-evoked increase in wheel counts > 10,000/6 h, and crouching/grimace, and compared across two groups: (1) KG, fed ketogenic food continuously (N = 25); and (2) CON, fed standard diet (N = 28).
RESULTS: 86% of CON versus none of the KG were crouching with grimace during ABA1. 93% of CON versus 11% of KG lost weight severely during ABA2 (p < 0.001, 8% difference of group mean weights). Severe hyperactivity was prevalent among CON (86%) and rare for KG (4%) during ABA2 (p < 0.001 on all food-restricted days). ABA up-regulated BDNF (brain-derived neurotrophic factor) in the hippocampus of both groups but ketone body, β-hydroxybutyrate, in urine was increased only among KG.
DISCUSSION: Ketogenic diet may reduce severity of AN relapse through reduction of compulsive exercise, via mechanisms that are in addition to BDNF up-regulation and involve β-hydroxybutyrate.

Keywords:  BDNF; activity‐based anorexia; anorexia nervosa; beta‐hydroxybutyrate; exercise; food restriction; food‐anticipatory activity; ketogenic diet; ketone bodies; wheel running

DOI:  https://doi.org/10.1002/eat.24323
JCI Insight. 2024 Nov 22. pii: e184279. [Epub ahead of print]9(22):

Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.

Andrew S Perry, Paolo Piaggi, Shi Huang, Matthew Nayor, Jane Freedman, Kari E North, Jennifer E Below, Clary B Clish, Venkatesh L Murthy, Jonathan Krakoff, Ravi V Shah.

  Human studies linking metabolism with organism-wide physiologic function have been challenged by confounding, adherence, and precisionHere, we united physiologic and molecular phenotypes of metabolism during controlled dietary intervention to understand integrated metabolic-physiologic responses to nutrition. In an inpatient study of individuals who underwent serial 24-hour metabolic chamber experiments (indirect calorimetry) and metabolite profiling, we mapped a human metabolome onto substrate oxidation rates and energy expenditure across up to 7 dietary conditions (energy balance, fasting, multiple 200% caloric excess overfeeding of varying fat, protein, and carbohydrate composition). Diets exhibiting greater fat oxidation (e.g., fasting, high-fat) were associated with changes in metabolites within pathways of mitochondrial β-oxidation, ketogenesis, adipose tissue fatty acid liberation, and/or multiple anapleurotic substrates for tricarboxylic acid cycle flux, with inverse associations for diets with greater carbohydrate availability. Changes in each of these metabolite classes were strongly related to 24-hour respiratory quotient (RQ) and substrate oxidation rates (e.g., acylcarnitines related to lower 24-hour RQ and higher 24-hour lipid oxidation), underscoring links between substrate availability, physiology, and metabolism in humans. Physiologic responses to diet determined by gold-standard human metabolic chambers are strongly coordinated with biologically consistent, interconnected metabolic pathways encoded in the metabolome.

Keywords:  Amino acid metabolism; Carbohydrate metabolism; Intermediary metabolism; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.184279
Expert Rev Hematol. 2024 Nov 18. 1-12

BCL-2 inhibition in acute myeloid leukemia: resistance and combinations.

Qi Zhang Tatarata, Zhe Wang, Marina Konopleva.

   INTRODUCTION: The introduction of venetoclax has revolutionized the treatment landscape of acute myeloid leukemia, offering new therapeutic opportunities. However, the clinical response to venetoclax varies significantly between patients, with many experiencing limited duration of response.
AREAS COVERED: Identified resistance mechanisms include both intrinsic and acquired resistance to VEN. The former is associated with cell lineage and differentiation state. The latter includes dependency on alternative BCL-2 family anti-apoptotic protein(s) mediated by genetic, epigenetic, or post-translational mechanisms, mitochondrial and metabolic involvement, as well as microenvironment. Understanding these mechanisms is crucial for optimizing venetoclax-based therapies and enhancing treatment outcomes for patients with acute myeloid leukemia. This review aims to elucidate the primary mechanisms underlying resistance to venetoclax and explore current therapeutic strategies to overcome this challenge.
EXPERT OPINION: In patients with venetoclax resistance, alternative options include targeted combination therapies tailored to individual cases based on cytogenetics and prior treatments. Many of these therapies require further clinical investigation to validate their safety and efficacy.

Keywords:  AML; Venetoclax; metabolism; mitochondria; resistance; signaling pathway

DOI:  https://doi.org/10.1080/17474086.2024.2429604
Nature. 2024 Nov 20.

Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.

Yu-Jung Chen, Swathi V Iyer, David Chun-Cheng Hsieh, Buren Li, Harold K Elias, Tao Wang, Jing Li, Mungunsarnai Ganbold, Michelle C Lien, Yu-Chun Peng, Xuanhua P Xie, Chenura D Jayewickreme, Marcel R M van den Brink, Sean F Brady, S Kyun Lim, Luis F Parada.

Glioblastoma is incurable and in urgent need of improved therapeutics1. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death2. Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin-adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD+ salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD+ pocket3. In vivo, gliocidin penetrates the blood-brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.

DOI: https://doi.org/10.1038/s41586-024-08224-z
Oncogene. 2024 Nov 20.

The influence of endothelial metabolic reprogramming on the tumor microenvironment.

Kelby Kane, Deanna Edwards, Jin Chen.

Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC's role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.

DOI: https://doi.org/10.1038/s41388-024-03228-5
BMC Biol. 2024 Nov 20. 22(1): 268

Systemic and transcriptional response to intermittent fasting and fasting-mimicking diet in mice.

Helene Michenthaler, Kalina Duszka, Isabel Reinisch, Markus Galhuber, Elisabeth Moyschewitz, Sarah Stryeck, Tobias Madl, Andreas Prokesch, Jelena Krstic.

   BACKGROUND: Dietary restriction (DR) has multiple beneficial effects on health and longevity and can also improve the efficacy of certain therapies. Diets used to instigate DR are diverse and the corresponding response is not uniformly measured. We compared the systemic and liver-specific transcriptional response to intermittent fasting (IF) and commercially available fasting-mimicking diet (FMD) after short- and long-term use in C57BL/6 J mice.
RESULTS: We show that neither DR regimen causes observable adverse effects in mice. The weight loss was limited to 20% and was quickly compensated during refeeding days. The slightly higher weight loss upon FMD versus IF correlated with stronger fasting response assessed by lower glucose levels and higher ketone body, free fatty acids and especially FGF21 concentrations in blood. RNA sequencing demonstrated similar transcriptional programs in the liver after both regimens, with PPARα signalling as top enriched pathway, while on individual gene level FMD more potently increased gluconeogenesis-related, and PPARα and p53 target gene expression compared to IF. Repeated IF induced similar transcriptional responses as acute IF. However, repeated cycles of FMD resulted in blunted expression of genes involved in ketogenesis and fatty acid oxidation.
CONCLUSIONS: Short-term FMD causes more pronounced changes in blood parameters and slightly higher weight loss than IF, while both activate similar pathways (particularly PPARα signalling) in the liver. On individual gene level FMD induces a stronger transcriptional response, whereas cyclic application blunts transcriptional upregulation of fatty acid oxidation and ketogenesis only in FMD. Hence, our comparative characterization of IF and FMD protocols renders both as effective DR regimens and serves as resource in the fasting research field.

Keywords:  Fasting-mimicking diet; Gene expression; Intermittent fasting; Metabolites; Mice; RNAseq; Systemic response; Transcription

DOI:  https://doi.org/10.1186/s12915-024-02061-2
ACS Appl Bio Mater. 2024 Nov 22.

Differential Effects of Confinement on the Dynamics of Normal and Tumor-Derived Pancreatic Ductal Organoids.

Jonah M Rosas, Joseph P Campanale, Jacob L Harwood, Lufei Li, Rachel Bae, Shujun Cheng, Julia M Tsou, Kathi M Kaiser, Dannielle D Engle, Denise J Montell, Angela A Pitenis.

  Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the epithelia comprising the ductal network of the pancreas. During disease progression, PDAC tumors recruit fibroblasts that promote fibrosis, increasing local tissue stiffness and subjecting epithelial cells to increased compressive forces. Previous in vitro studies have documented cytoskeletal and nuclear adaptation following compressive stresses in two-dimensional (2D) and three-dimensional (3D) environments. However, a comparison of the responses of normal and tumor-derived ductal epithelia to physiologically relevant confinement remains underexplored, especially in 3D organoids. Here we control confinement with an engineered 3D microenvironment composed of Matrigel mixed with a low yield stress granular microgel. Normal and tumor-derived murine pancreas organoids (normal and tumor) were cultured for 48 h within this composite 3D environment or in pure Matrigel to investigate the effects of confinement on morphogenesis and lumen expansion. In confinement, tumor organoids (mT) formed a lumen that expanded rapidly, whereas normal organoids (mN) expanded more slowly. Moreover, a majority of normal organoids in more-confined conditions exhibited an inverted apicobasal polarity compared to those in less-confined conditions. Tumor organoids exhibited a collective "pulsing" behavior that increased in confinement. These pulses generated forces sufficient to locally overcome the yield stress of the microgels in the direction of organoid expansion. Normal organoids more commonly exhibit unidirectional rotation. Our in vitro microgel confinement platform enabled the discovery of two distinct modes of collective force generation in organoids that may shed light on the mutual interactions between tumors and the microenvironment. These insights into in vitro dynamics may deepen our understanding of how the confinement of healthy cells within a fibrotic tumor niche disrupts tissue organization and function in vivo.

Keywords:  apicobasal polarity; confinement; microgel–Matrigel composite; pancreatic ductal organoids; size oscillations; tumor microenvironment

DOI:  https://doi.org/10.1021/acsabm.4c01301
Neurochem Res. 2024 Nov 16. 50(1): 13

ATP Restoration by ATP-Deprived Cultured Primary Astrocytes.

Gabriele Karger, Johanna Elisabeth Willker, Antonia Regina Harders, Patrick Watermann, Ralf Dringen.

  A high cellular concentration of adenosine triphosphate (ATP) is essential to fuel many important functions of brain astrocytes. Although cellular ATP depletion has frequently been reported for astrocytes, little is known on the metabolic pathways that contribute to ATP restoration by ATP-depleted astrocytes. Incubation of cultured primary rat astrocytes in glucose-free buffer for 60 min with the mitochondrial uncoupler BAM15 lowered the cellular ATP content by around 70%, the total amount of adenosine phosphates by around 50% and the adenylate energy charge (AEC) from 0.9 to 0.6. Testing for ATP restoration after removal of the uncoupler revealed that the presence of glucose as exclusive substrate allowed the cells to restore within 6 h around 80% of the initial ATP content, while coapplication of adenosine plus glucose enabled the cells to fully restore their initial ATP content within 60 min. A rapid but incomplete and transient ATP restoration was found for astrocytes that had been exposed to adenosine alone. This restoration was completely prevented by application of the pyruvate uptake inhibitor UK5099, the respiratory chain inhibitor antimycin A or by the continuous presence of BAM15. However, the presence of these compounds strongly accelerated the release of lactate from the cells, suggesting that the ribose moiety of adenosine can serve as substrate to fuel some ATP restoration via mitochondrial metabolism. Finally, the adenosine-accelerated ATP restoration in glucose-fed astrocytes was inhibited by the presence of the adenosine kinase inhibitor ABT-702. These data demonstrate that astrocytes require for a rapid and complete ATP restoration the presence of both glucose as substrate and adenosine as AMP precursor.

Keywords:  ATP restoration; Adenosine; Astrocytes; Glycolysis; Metabolism; Mitochondria

DOI:  https://doi.org/10.1007/s11064-024-04276-9
Nat Med. 2024 Nov 22.

Obesity predisposes to specific cancer driver mutations.

Karen O'Leary.



Keywords:  Cancer; Genomics; Obesity

DOI:  https://doi.org/10.1038/d41591-024-00080-8
PLoS One. 2024 ;19(11): e0311345

Glycemic load impacts the response of acquired resistance in breast cancer cells to chemotherapeutic drugs in vitro.

Sirin A Adham, Azza Al Kalbani, Noura Al Zeheimi, Muna Al Dalali, Noor Al Kharusi, Azeeza Siddiqi, Aliya Al Maskari.

Resisting chemotherapy is a significant hurdle in treating breast cancer. Locally advanced breast cancer patients undergo four cycles of Adriamycin and Cyclophosphamide, followed by four cycles of Paclitaxel before surgery. Some patients resist this regimen, and their cancer recurred. Our study aimed to understand the underlying mechanisms of acquired resistance during these specific treatment phases. We explored how breast cancer cells, resistant to chemotherapy, respond to different glucose levels, shedding light on the intricate relationship between diabetes, breast cancer subtype, and resistance to preoperative chemotherapy. We examined two groups of cell lines: the standard MDA-MB-231 and MCF7 cells and their resistant counterparts after exposure to four cycles of Adriamycin and cyclophosphamide (4xAC) or four cycles of 4xAC and Paclitaxel (4xAC+4xPAC), aiming to unravel the mechanisms and cellular responses at these critical treatment stages. Notably, under normal and low glucose conditions, the resistant MDA-MB-231 cells showed accelerated growth compared to the control cells, while the resistant MCF7 cells proliferated more slowly than their original counterparts. Resistance to 4xAC resulted in significant cell death in both cell lines, especially under low glucose conditions, in contrast to control or 4xAC+4xPAC-resistant cells. The similarity between the MCF7 4xAC+4xPAC resistant cells and the control might be due to the P-AKT expression pattern in response to glucose levels since the levels were constant in MCF7 4xAC in all glucose concentrations. Molecular analysis revealed specific protein accumulations explaining the heightened proliferation and invasion in resistant MDA-MB-231 cells and their ability to withstand low glucose levels compared to MCF7. In conclusion, increased drug involvement corresponds to increased cell resistance, and changes in glucose levels differentially impact resistant variant cells to different drugs. The findings can be translated clinically to explain patients' differential responses to preoperative chemotherapy cycles considering their breast cancer subtype and diabetic status.

DOI: https://doi.org/10.1371/journal.pone.0311345
Exp Neurol. 2024 Nov 18. pii: S0014-4886(24)00390-X. [Epub ahead of print] 115064

Diminished lactate utilization in LDHB-deficient neurons leads to impaired long-term memory retention.

Jin Soo Lee, Bok Seon Yoon, Songmi Han, Yihyang Kim, Chan Bae Park.

  Neurons' high energy demands for processing, transmitting, and storing information in the brain necessitate efficient energy metabolism to maintain normal neuronal function. The astrocyte-neuron lactate shuttle (ANLS) hypothesis suggests neurons preferentially use lactate from astrocytes over glucose for energy. This study investigated lactate dehydrogenase B (LDHB), which preferentially converts lactate to pyruvate, in neuronal energy metabolism and cognitive function. LDHB-deficient neurons showed reduced lactate-driven energy metabolism in culture, while LDHB-deficient brains accumulated lactate, both indicating decreased lactate utilization. This reduced lactate utilization was correlated with impaired long-term memory in LDHB-deficient mice, while short-term memory remained unaffected and overall neuropathology was only mildly disturbed. Unexpectedly, LDHB-deficient neurons maintain stable energy metabolism under physiological glucose conditions, indicating the presence of lactate dehydrogenase (LDH) activity in LDHB-deficient neurons. The observation of lactate dehydrogenase A (LDHA), which preferentially converts pyruvate to lactate but can also catalyze the reverse reaction less efficiently, in LDHB-deficient neurons may explain their stable energy metabolism and reduced lactate utilization. This study challenges the established concept of strict LDH isoform compartmentalization in brain cells, questioning the exclusive presence of LDHB in neurons and suggesting a more flexible neuronal metabolic profile than previously assumed by the ANSL hypothesis.

Keywords:  Astrocyte-neuron lactate shuttle; Lactate; Lactate dehydrogenase B; Long-term memory retention; Metabolic compartmentalization

DOI:  https://doi.org/10.1016/j.expneurol.2024.115064
Am J Physiol Cell Physiol. 2024 Nov 21.

The impact of diet induced obesity on 5 fluorouracil-induced tumor and liver immune cell cytotoxicity.

Brandon N VanderVeen, Thomas D Cardaci, Brooke M Bullard, Christian A Unger, Jeffrey C Freeman, Reilly T Enos, Michael Shtutman, Michael D Wyatt, Daping Fan, E Angela Murphy.

  Obesity increases the risk for developing several cancers, including colorectal cancer (CRC), and is associated with liver perturbations which likely impacts treatment tolerance. 5 fluorouracil (5FU) remains a first line treatment for CRC, but efficacy is hampered by interpatient variable responsiveness and off target toxicities. The current study examined the impact of diet-induced obesity (DIO) on 5FU cytopenia and efficacy using two established CRC models: MC38 (C57BL/6) and C26 (CD2F1). DIO increased tumor size in both MC38 and C26. DIO reduced liver dihydropyrimidine dehydrogenase (dpyd) expression, the enzyme that catalyzes 5FUs catabolism to become inactive, in MC38 mice, but not C26. 5FU remained efficacious against early MC38 and C26 tumor growth; however, 5FU-induced tumor and liver immune cell death was exacerbated following 3 cycles of 5FU with MC38. DIO caused dramatic changes to liver Kupffer Cells (KC), wherein there were increased pro-metastatic, immunosuppressive KCs in Obese Control and MC38. 5FU, however, depleted these KCs and increased inflammatory KCs in both Lean and Obese MC38. DIO yielded a milder obesity phenotype in CD2F1 mice, and 5FU-induced cytopenia was not different between Lean and Obese. DIO increased total liver KCs, however, C26 tumors increased liver KCs, which were normalized with 5FU treatment, irrespective of DIO. While 5FU remained efficacious in both models of CRC and did not reduce survival, multiple cycles of 5FU monotherapy increased liver and tumor immune cell death in DIO mice. Altogether, obesity was not protective, but rather exacerbated chemotherapy-induced cytotoxicity and promoted a pro-metastatic liver environment.

Keywords:  Kupffer Cells; chemotherapy; colon cancer; metabolism; tumor associated macrophages

DOI:  https://doi.org/10.1152/ajpcell.00687.2024
BMC Gastroenterol. 2024 Nov 21. 24(1): 419

The association between non- and pro-healthy diet indices and the risk of colorectal cancer: a case-control study.

Maryam Ranjbar Zahedani, Iman Kazemi, Ali Kohanmoo, Zainab Shateri, Mohammad Mahdi Rajabpour, Mehran Nouri, Bahram Rashidkhani.

   BACKGROUND: The Non-Healthy Diet Index (NHDI) and the Pro-Healthy Diet Index (PHDI) are two novel indices that evaluate the healthiness of a diet based on the consumption of several food groups. This study aimed to evaluate the association between adherence to the PHDI and NHDI and colorectal cancer (CRC) risk in the Iranian population.
METHODS: The current study was conducted as a hospital-based research using a case (n = 71)- matched-controls (n = 142) design in Tehran, Iran. A semi-quantitative food frequency questionnaire was utilized to determine participants' dietary intake after confirming the diagnosis of CRC and at the time of the interview. The PHDI-10 was employed to assess the consumption of foods with positive health effects, which is linked to the frequency of consuming 10 food groups, and the NHDI-14 was used to assess the consumption of foods that have detrimental effects on health, based on the frequency of 14 food groups. Logistic regression was used to evaluate the association between continuous PHDI and NHDI scores and their tertiles with CRC.
RESULTS: The results indicated that individuals in the highest tertile of the PHDI showed a lower CRC risk compared to those in the lowest tertile (adjusted model- odds ratio (OR) = 0.25; 95% confidence interval (CI): 0.10-0.61; P = 0.002). Also, lower odds of CRC risk were seen with each unit change in the total score of PHDI in the adjusted model (OR = 0.86; 95% CI: 0.76-0.96; P = 0.009). In contrast, individuals in the highest tertile of the NHDI showed a higher risk of CRC compared to those in the lowest tertile (OR = 2.62; 95% CI: 1.09-6.27; P = 0.030) in the adjusted model. Also, higher odds of CRC risk were observed with each unit increase in the total score of NHDI in the adjusted model (OR = 1.13; 95% CI: 1.03-1.25; P = 0.008).
CONCLUSIONS: The present study showed that higher adherence to PHDI and NHDI is associated with lower and higher CRC risk, respectively. These results provide valuable insights into the roles of healthy and unhealthy diets in CRC prevention.

Keywords:  Colorectal neoplasms; Diet index; Diet quality; Iran

DOI:  https://doi.org/10.1186/s12876-024-03520-4
bioRxiv. 2024 Oct 29. pii: 2024.10.24.620086. [Epub ahead of print]

Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting.

Michael E Ponte, John C Prom, Mallory A Newcomb, Annabelle B Jordan, Lucas L Comfort, Jiayin Hu, Patrycja Puchalska, Caroline E Geisler, Matthew R Hayes, E Matthew Morris.

The capacity of the liver to serve as a peripheral sensor in the regulation of food intake has been debated for over half a century. The anatomical position and physiological roles of the liver suggest it is a prime candidate to serve as an interoceptive sensor of peripheral tissue and systemic energy state. Importantly, maintenance of liver ATP levels and within- meal food intake inhibition is impaired in human subjects with obesity and obese pre- clinical models. We demonstrate that decreased hepatic mitochondrial energy metabolism in liver-specific, heterozygous PGC1a mice results in reduced mitochondrial response to changes in ΔGATP and tissue ATP following fasting. These impairments in liver energy state are associated with larger and longer meals during chow feeding, impaired dose-dependent food intake inhibition in response to mixed and individual nutrient oral pre-loads, and greater acute fasting-induced food intake. These data support previous work proposing liver-mediated food intake regulation through modulation of peripheral satiation signals.

DOI: https://doi.org/10.1101/2024.10.24.620086
Blood Cancer J. 2024 Nov 19. 14(1): 202

What have we learned about TP53-mutated acute myeloid leukemia?

Moazzam Shahzad, Muhammad Kashif Amin, Naval G Daver, Mithun Vinod Shah, Devendra Hiwase, Daniel A Arber, Mohamed A Kharfan-Dabaja, Talha Badar.

TP53 is a tumor suppressor gene frequently mutated in human cancers and is generally associated with poor outcomes. TP53 mutations are found in approximately 5% to 10% of patients with de novo acute myeloid leukemia (AML), more frequently observed in elderly patients and those with therapy-related AML. Despite recent advances in molecular profiling and the emergence of targeted therapies, TP53-mutated AML remains a challenge to treat. Current treatment strategies, including conventional chemotherapy, hypomethylating agents, and venetoclax-based therapies, have shown limited efficacy in TP53-mutated AML, with low response rates and poor overall survival. Allogeneic hematopoietic stem cell transplantation is a potentially curative option; however, its efficacy in TP53-mutated AML depends on comorbid conditions and disease status at transplantation. Novel therapeutic modalities, including immune-based therapies, did show promise in early-phase studies but did not translate into effective therapies in randomized controlled trials. This review provides a comprehensive overview of TP53 mutations in AML, outcomes based on allelic burden, clinical implications, and therapeutic challenges.

DOI: https://doi.org/10.1038/s41408-024-01186-5
Leukemia. 2024 Nov 20.

Global patterns of leukemia by subtype, age, and sex in 185 countries in 2022.

Dagrun S Daltveit, Eileen Morgan, Murielle Colombet, Eva Steliarova-Foucher, Karima Bendahhou, Rafael Marcos-Gragera, Zheng Rongshou, Alexandra Smith, Hui Wei, Isabelle Soerjomataram.

In 2022, leukemia ranked as the second most common hematological malignancy after non-Hodgkin lymphoma worldwide. However, updated global estimates of leukemia incidence by subtype are unavailable. We estimated leukemia incidences for different leukemia subtypes by country, world region, and human developmental index using data from the Cancer Incidence in Five Continents databases combined with the GLOBOCAN 2022 estimates of leukemia in 185 countries. We estimated sex-specific age-standardized rates (ASRs) per 100 000 for children (0-19 years) and adults (20+ years). In adults, the most common leukemia worldwide was AML (males: 38%, ASR = 3·1; females: 43%, ASR = 2·4), followed by CLL (males: 28%, ASR = 2·2; females: 24%, ASR = 1·3). In very high HDI countries, the ASR of CLL was higher than the ASR of AML among males (5·2 versus 4·3, respectively) and similar among females (2·9 and 3·0, respectively). In children, the most common leukemia was ALL (boys: 70%, ASR = 2·4; girls: 68%, ASR = 1·8) followed by AML (boys: 22%, ASR = 0·76; girls: 25%, ASR = 0·65). ALL proportions varied across world sub-regions from 57 to 78% among boys, and from 49 to 80% among girls. Our findings suggest clear geographical patterns of leukemia subtypes in adults and children. Further research into underlying causes that explain these variations is needed to support cancer control strategies for prevention and plan national healthcare needs.

DOI: https://doi.org/10.1038/s41375-024-02452-y
Worldviews Evid Based Nurs. 2024 Nov 21.

Effectiveness of resistance training in preventing sarcopenia among breast cancer patients undergoing chemotherapy: A systematic review and meta-analysis.

Ting-Wan Tan, Han-Ling Tan, Yu-Chu Chung.

   BACKGROUND: Breast cancer patients undergoing chemotherapy experience body composition changes impacting treatment outcomes. The role of resistance training in mitigating chemotherapy-induced sarcopenia in breast cancer patients is not well defined.
AIMS: This study aims to assess the efficacy of resistance training in preventing sarcopenia among breast cancer patients undergoing chemotherapy.
METHODS: A systematic search was conducted across PubMed, EMBASE, Medline, the Cochrane Library, and CINAHL until May 5, 2023. Selected literature focused on the effects of resistance training on body fat, muscle mass, muscle strength, and physical performance in breast cancer patients undergoing chemotherapy. Cochrane Risk of Bias tool version 2.0 was employed for quality assessment, and data were analyzed using Comprehensive Meta-Analysis version 2.0.
RESULTS: Eleven randomized controlled trials (RCTs) showed that resistance training had a significant positive impact on reducing body fat (SMD = -0.250, 95% CI [-0.450, -0.050]), increasing lean body mass (SMD = 0.374, 95% CI [0.178, 0.571]), and enhancing handgrip strength at both the affected site (SMD = 0.326, 95% CI [0.108, 0.543]) and the nonaffected site (SMD = 0.276, 95% CI [0.059, 0.492]). Additionally, significant improvements were observed in leg press strength (SMD = 0.598, 95% CI [0.401, 0.796]) and overall physical performance (SMD = 0.671, 95% CI [0.419, 0.923]).
LINKING EVIDENCE TO ACTION: Resistance training is a recommended intervention for reducing body fat, increasing muscle mass, muscle strength, and enhancing physical performance in breast cancer patients undergoing chemotherapy. Ideal low-intensity resistance training programs span 8-24 weeks, with 20-to-90-min sessions 2-4 times weekly. Regimens generally entail 8-12 repetitions at 40%-90% of one-repetition maximum test, with free-weight resistance training targeting major muscle groups yielding substantial benefits. Further research should explore outcomes across different chemotherapy phases and investigate long-term resistance training effects for a comprehensive view.

Keywords:  breast cancer; chemotherapy; meta‐analysis; resistance exercise; sarcopenia

DOI:  https://doi.org/10.1111/wvn.12756
Biochem Biophys Res Commun. 2024 Nov 15. pii: S0006-291X(24)01544-4. [Epub ahead of print]739 151008

High-iron diet damages brown adipose tissue mitochondria and exacerbates metabolic hazards of a high-fat diet.

Yifan Zhang, Zhenzhong Bai, Kang Song, Ying Liu, Wenbin Zhang.

  Metabolic diseases may be prevented by reducing carbohydrate intake and replacing plant-based diets with animal-based ones low in carbohydrates but high in protein, fat, and iron. While the effects of sugars on metabolic diseases are well-known, the role of iron remains unclear. This study aimed to explore the effects of a high-fat high-iron animal diet on body metabolism in mice. Micro-PET imaging was used to assess 18-F-labelled glucose uptake in BAT, and the morphology, respiratory function, and oxidative stress of BAT mitochondria were examined. The underlying mechanisms were elucidated by analyzing the expression of UCP-1, PGC-1α and PPARα. The high-iron high-fat diet increased appetite, impaired glucose tolerance, and reduced insulin sensitivity. Additionally, the high-iron diet promoted gluconeogenesis only in the absence of high-fat levels. Both high-iron and high-fat diets suppressed BAT activity, increased mitochondrial oxidative stress, decreased mitochondrial respiratory function, and lowered thermogenic gene expression. Weight loss strategies focusing solely on reducing carbohydrates and increasing animal foods, like ketogenic diets, may have long-term detrimental effects on metabolic health. Prioritizing dietary diversity and monitoring overall caloric intake is advisable for optimal outcomes.

Keywords:  Adipose tissue; Animal-based diet; Insulin sensitivity; Iron overload; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1016/j.bbrc.2024.151008
Mol Cell Biochem. 2024 Nov 22.

Research advances in branched-chain amino acid metabolism in tumors.

Zheng Li, Sainan Chen, Xuechao Wu, Fei Liu, Jing Zhu, Jiayi Chen, Xiaojie Lu, Rui Chi.

  The metabolic reprogramming of amino acids is an important component of tumor metabolism. Branched-chain amino acids (BCAAs) perform important functions in tumor progression. They are the important amino donor and are involved in the synthesis of various non-essential amino acids, nucleotides, and polyamines to satisfy the increased demand for nitrogen sources. This review summarizes the studies related to abnormalities in BCAA metabolism during tumorigenesis and the potential therapeutic targets. The expression of BCAA transporters was significantly upregulated in tumor cells, which increases BCAA uptake. High expression of the BCAA transaminases is prevalent in various tumors, however, the dehydrogenation step of BCAA catabolism is inhibited in tumors. This review shows that BCAA metabolic reprogramming is an important tumor metabolic feature, and metabolic genes of BCAAs play a crucial role in tumor metabolism, representing a good auxiliary target for early clinical diagnosis and treatment. In addition, BCAAs are indispensable for maintaining immune system function, and dietary supplementation with BCAAs can enhance the activity of immune cells. Therefore, BCAA supplementation in tumor patients may affect the interaction between the immune system and tumors.

Keywords:  Branched-chain amino acids; Immunity; Metabolism; Tumor

DOI:  https://doi.org/10.1007/s11010-024-05163-1
Expert Rev Proteomics. 2024 Nov 22. 1-14

Proteogenomic profiling of acute myeloid leukemia to identify therapeutic targets.

Heather C Murray, Jonathan Sillar, Maddison Chambers, Nicole M Verrills.

   INTRODUCTION: Acute myeloid leukemia (AML) is an aggressive and poor-prognosis blood cancer. Despite a low mutation burden compared to other cancers, AML is heterogenous and identifying robust therapeutic targets has been difficult. Genomic profiling has greatly advanced our understanding of AML, and has revealed targets for AML therapy. However, only 50% of AML patients have gene mutations that are currently druggable, and relapse rates remain high. The addition of proteomic profiling is emerging to address these challenges.
AREAS COVERED: Using references collected through Pubmed, we review recent studies that have combined genomic and proteomic profiling (i.e. proteogenomic profiling), as well as studies that have additionally integrated other omics approaches, such as phosphoproteomics. We highlight how proteogenomic profiling promises to deconvolve the cellular pathways driving leukemogenesis, uncover novel therapeutic targets, and identify biomarkers of response to novel and existing therapies.
EXPERT OPINION: Proteogenomic profiling is providing unparalleled insight into AML, and is beginning to identify robust biomarkers. Standardization of workflows will be required before mass spectrometry-based proteomic assays can be integrated into routine clinical use. However, the demonstrated ability to adapt signatures into biomarker panels that can be assayed by existing clinical workflows is enabling current clinical translation.

Keywords:  Acute myeloid leukemia; biomarkers; phosphoproteomics; precision therapy; proteogenomics; proteomics

DOI:  https://doi.org/10.1080/14789450.2024.2431272
Eur J Nutr. 2024 Nov 21. 64(1): 13

Plasma metabolite profiles related to dietary patterns: exploring the association with colorectal tumor risk.

Jingjing Ni, Haojie Lu, Weiyi Chen, Yingying Zhao, Shuaishuai Yang, Jia Zhang, Zhen Wang, Yuting Shi, Jing Yi, Jia Li, Xuemei Song, Yuxin Ni, Sijia Zhu, Zhihao Zhang, Li Liu.

   BACKGROUND: Multiple diet patterns play a crucial role in the development of colorectal cancer and its precursor, colorectal adenoma, but mediating effect of plasma metabolite profiles is unclear.
METHODS: A total of 95,275 participants from UK Biobank with plasma metabolomics and dietary information were analyzed. Metabolite profile scores for 14 dietary patterns were estimated through elastic net regression. Cox regression analysis assessed the associations of dietary patterns and their metabolite profile scores with colorectal tumor risk. Mediating effects of identified metabolite profile scores were estimated in the associations.
RESULTS: Fourteen metabolite profile scores, including a range of 28 to 205 signatures, were weak to moderate correlation with dietary patterns (all p < 0.001). Multivariable Cox regression analyses revealed that five dietary patterns were significantly correlated with a decreased risk of colorectal tumor after FDR correction and adjustment for covariates. HRs (95% CIs) per 1 SD for these diet patterns were as follows: WCRF (0.93, 0.90-0.96), CRC score (0.94, 0.92-0.97), AHEI-2010 (0.95, 0.92-0.97), DASH (0.94, 0.91-0.97), and hPDI (0.95, 0.93-0.98). Similarly, metabolite profile scores for these five dietary patterns were inversely associated with colorectal tumor risk, with HRs (95% CIs) per 1 SD as follows: WCRF (0.59, 0.49-0.70), CRC score (0.67, 0.58-0.77), AHEI-2010 (0.73, 0.65-0.80), DASH (0.75, 0.66-0.84), and hPDI (0.56, 0.47-0.67). The mediation proportions of five metabolite profile scores between dietary patterns and colorectal tumor risk ranged from 6.37 to 27.23% (all p < 0.001).
CONCLUSIONS: Five dietary patterns and their metabolite profile scores, were inversely correlated with colorectal tumor risk. These findings highlight the potential of metabolite profiles as mediators in the association between dietary patterns and the risk of colorectal tumor, further contributing to the prevention of colorectal cancer or adenoma and providing new insights for future research.

Keywords:  Colorectal tumor; Dietary pattern; Mediating effect; Metabolomics; Prospective study

DOI:  https://doi.org/10.1007/s00394-024-03527-3
Eur J Nutr. 2024 Nov 21. 64(1): 15

Association of low-carbohydrate diet score and carbohydrate quality index with colorectal cancer risk: a large-scale case-control study.

Fang-Ting Lin, Ke-Xin Tu, Qing-Jian Ou, Xue-Qing Deng, Yu-Jing Fang, Cai-Xia Zhang.

   PURPOSE: Carbohydrate intake has been linked to colorectal cancer (CRC) risk, with variations depending on the quantity and quality of carbohydrates consumed. This study aimed to investigate the association between carbohydrate quantity and quality, using the low-carbohydrate diet score (LCD) and carbohydrate quality index (CQI), and the risk of CRC in the Chinese population.
METHODS: We conducted a case-control study in Guangzhou, China, with 2,799 CRC cases and an equal number of sex- and age-matched controls. Dietary data were collected using a validated food frequency questionnaire to derive the LCD and CQI, assessing the quantity and quality of carbohydrate intake separately. Odds ratios (OR) and 95% confidence interval (CI) for CRC risk were estimated using unconditional logistic regression models, and restricted cubic splines were used to explore potential non-linear relationships.
RESULTS: The results demonstrated that higher adherence to the overall LCD score, plant-based LCD score, and CQI was associated with a lower risk of CRC. The adjusted ORs (95%CIs) for the highest quintile of intake in comparison with the lowest quintile were 0.76 (0.63, 0.91) for the overall LCD score, 0.61 (0.50, 0.74) for the plant-based LCD score, and 0.70 (0.58,0.84) for the CQI, respectively. However, the animal-based LCD did not show a significant association with CRC risk, with the adjusted OR (95%CI) for the highest quintile compared to the lowest being 0.98 (0.81, 1.18). Restricted cubic splines analysis showed non-linear associations of the overall LCD score, animal-based LCD score, and plant-based LCD score with CRC risk. In contrast, a linear relationship was observed between CQI and CRC risk (Pnonlinear = 0.594).
CONCLUSIONS: Our findings indicate that the overall LCD score, the plant-based LCD score, and the CQI were inversely associated with the risk of CRC.

Keywords:  Carbohydrate intake; Carbohydrate quality index; Colorectal cancer; Low-carbohydrate diet score

DOI:  https://doi.org/10.1007/s00394-024-03533-5
Cancer Metab. 2024 Nov 19. 12(1): 35

Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.

Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto.

   BACKGROUND: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.
METHODS: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.
RESULTS: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.
CONCLUSIONS: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.

Keywords:  Glioblastoma; Glutaminolysis; Metabolic changes; Mitochondria

DOI:  https://doi.org/10.1186/s40170-024-00364-0
Mol Neurobiol. 2024 Nov 19.

The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration.

Patrick C Bradshaw, Jessa L Aldridge, Leah E Jamerson, Canah McNeal, A Catherine Pearson, Chad R Frasier.

  Cardiolipin (CL) is an essential phospholipid that supports the functions of mitochondrial membrane transporters and oxidative phosphorylation complexes. Due to the high level of fatty acyl chain unsaturation, CL is prone to peroxidation during aging, neurodegenerative disease, stroke, and traumatic brain or spinal cord injury. Therefore, effective therapies that stabilize and preserve CL levels or enhance healthy CL fatty acyl chain remodeling are needed. In the last few years, great strides have been made in determining the mechanisms through which precursors for CL biosynthesis, such as phosphatidic acid (PA), are transferred from the ER to the outer mitochondrial membrane (OMM) and then to the inner mitochondrial membrane (IMM) where CL biosynthesis takes place. Many neurodegenerative disorders show dysfunctional mitochondrial ER contact sites that may perturb PA transport and CL biosynthesis. However, little is currently known on how neuronal mitochondria regulate the synthesis, remodeling, and degradation of CL. This review will focus on recent developments on the role of CL in neurological disorders. Importantly, due to CL species in the brain being more unsaturated and diverse than in other tissues, this review will also identify areas where more research is needed to determine a complete picture of brain and spinal cord CL function so that effective therapeutics can be developed to restore the rates of CL synthesis and remodeling in neurological disorders.

Keywords:  Alzheimer’s; Cardiolipin; Cell death; Inflammation; Mitochondria; Parkinson’s

DOI:  https://doi.org/10.1007/s12035-024-04630-6
Endocr Connect. 2024 Nov 01. pii: EC-24-0336. [Epub ahead of print]

A novel approach to regulate glucose uptake in an anaplastic thyroid cancer cell line.

Shabnam Heydarzadeh, Ali Asghar Moshtaghie, Maryam Daneshpour, Mehdi Hedayati.

AIMS AND BACKGROUND: Curcumin's function in affecting cancer metabolic reprogramming remains poorly understood. Herein, we aimed to elucidate a novel link between Curcumin and the glucose uptake metabolism and glucose transporters (GLUTs) status in SW1736 cell line derived from anaplastic thyroid cancer.
MATERIALS AND METHODS: TheMTT test and flow cytometry was employed to test cell viability and cell death. For glucose uptake detection, ''GOD-PAP'' enzymatic colorimetric assay was applied to measure the direct glucose levels inside of the cells. Determination of GLUT1 and GLUT3 mRNA and protein expression in SW1736 cells was performed by qRT-PCR and western blotting. Also, the scratch wound healing assay was conducted for cell migration.
RESULTS: The data indicated that Curcumin-induced cell death is independent of apoptosis in this type of thyroid cancer cell line. Furthermore, significantly reduced GLUT1 and GLUT3 expression was observed after treatment with Curcumin, resulting in the inhibition of glucose uptake (p < 0.05). Scratch assay indicated the inhibition of cell migration in SW1736 cells treated by Curcumin (p < 0.05).
CONCLUSION: It can be concluded that GLUTs as metabolic targets can be blocked specifically by Curcumin for thyroid cancer prevention. Curcumin, as a promising anti-cancer agent, inhibits the growth of SW1736 anaplastic thyroid cancer cell line by regulating glucose uptake pathway and cell death. Altogether, these results suggest that the glucose pathway may be an important target for therapeutic intervention to sensitize tumor cells to cell death process by inhibition of glucose transporters.

DOI: https://doi.org/10.1530/EC-24-0336
Sci Rep. 2024 11 16. 14(1): 28296

Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.

Kaade Edgar, Mausbach Simone, Erps Nina, Sylvester Marc, Shakeri Farhad, Ron D Jachimowicz, Gieselmann Volkmar, Thelen Melanie.

Lysosomes play a crucial role in metabolic adaptation to starvation, but detailed in vivo studies are scarce. Therefore, we investigated the changes of the proteome of liver lysosomes in mice starved short-term for 6h or long-term for 24h. We verified starvation-induced catabolism by weight loss, ketone body production, drop in blood glucose and an increase of 3-methylhistidine. Deactivation of mTORC1 in vivo after short-term starvation causes a depletion of mTORC1 and the associated Ragulator complex in hepatic lysosomes, resulting in diminished phosphorylation of mTORC1 target proteins. While mTORC1 lysosomal protein levels and activity in liver were restored after long-term starvation, the lysosomal levels of Ragulator remained constantly reduced. To determine whether this mTORC1 activity pattern may be organ-specific, we further investigated the key metabolic organs muscle and brain. mTORC1 inactivation, but not re-activation, occurred in muscle after a starvation of 12 h or longer. In brain, mTORC1 activity remained unchanged during starvation. As mTORC1 deactivation is known to induce autophagy, we further investigated the more than 150 non-lysosomal proteins enriched in the lysosomal fraction upon starvation. Proteasomal, cytosolic and peroxisomal proteins dominated after short-term starvation, while after long-term starvation, mainly proteasomal and mitochondrial proteins accumulated, indicating ordered autophagic protein degradation.

DOI: https://doi.org/10.1038/s41598-024-78873-7
Pediatr Blood Cancer. 2024 Nov 20. e31450

Hypoalbuminemia and Nutritional Status in Children with Cancer.

Thomas W McLean, Natasha S Shah, Ronald D Barr, Janet A Tooze.

   BACKGROUND: In children with cancer, poor nutritional status adversely affects outcomes. Hypoalbuminemia is common in pediatric oncology patients, and in some groups is associated with inferior survival rates. We sought to determine if serum albumin associates with body mass index (BMI) percentile and if combining serum albumin and BMI is associated with survival.
METHODS: We performed a single institution, retrospective review of pediatric oncology patients and collected data regarding baseline BMI, serum albumin, and survival outcome. Combining baseline BMI and serum albumin, we classified patients' nutritional status as adequately nourished, mildly/moderately depleted, and severely depleted.
RESULTS: In a cohort of 490 pediatric oncology patients, hypoalbuminemia prevalence was 49%. Serum albumin did not associate with BMI percentile for age. Overall, those defined as severely depleted had an increased risk of relapse or death at 3 and 6 months from chemotherapy initiation compared with those defined as adequately nourished (hazard ratio [HR] = 2.37, 95% CI 1.29-4.37 at 3 months, p = 0.006; HR = 1.77, CI 1.11-2.82 at 6 months, p = 0.017). Statistical analyses suggest the inferior survival in those deemed severely depleted was primarily driven by hypoalbuminemia rather than BMI.
CONCLUSIONS: In this cohort of pediatric oncology patients, serum albumin did not correlate with BMI. Severe hypoalbuminemia is an adverse prognostic factor. Baseline BMI had a minimal impact on relapse-free survival and overall survival, independently or in combination with hypoalbuminemia.

Keywords:  albumin; body mass index; cancer; hypoalbuminemia; pediatric

DOI:  https://doi.org/10.1002/pbc.31450
Cell Rep Methods. 2024 Nov 18. pii: S2667-2375(24)00292-3. [Epub ahead of print]4(11): 100902

Development of fluorescence lifetime biosensors for ATP, cAMP, citrate, and glucose using the mTurquoise2-based platform.

Chongxia Zhong, Satoshi Arai, Yasushi Okada.

  Single-fluorescent protein (FP)-based FLIM (fluorescence lifetime imaging microscopy) biosensors can visualize intracellular processes quantitatively. They require a single wavelength for detection, which facilitates multi-color imaging. However, their development has been limited by the absence of a general design framework and complex screening processes. In this study, we engineered FLIM biosensors for ATP (adenosine triphosphate), cAMP (cyclic adenosine monophosphate), citrate, and glucose by inserting each sensing domain into mTurquoise2 (mTQ2) between Tyr-145 and Phe-146 using peptide linkers. Fluorescence intensity-based screening yielded FLIM biosensors with a 0.5 to 1.0 ns dynamic range upon analyte binding, demonstrating that the mTQ2(1-145)-GT-X-EF-mTQ2(146-238) backbone is a versatile platform for FLIM biosensors, allowing for simple intensity-based screening while providing dual-functional biosensors for both FLIM and intensity-based imaging. As a proof of concept, we monitored cAMP and Ca2+ dynamics simultaneously in living cells by dual-color imaging. Our results complement recent studies, establishing mTQ2 as a valuable framework for developing FLIM biosensors.

Keywords:  ATP; CP: Imaging; FLIM; biosensors; cAMP; citrate; fluorescence lifetime imaging microscopy; fluorescent protein; glucose; quantitative imaging

DOI:  https://doi.org/10.1016/j.crmeth.2024.100902
bioRxiv. 2024 Oct 29. pii: 2024.10.26.620422. [Epub ahead of print]

DNA methylation stochasticity is linked to transcriptional variability and identifies convergent epigenetic disruption across genetically-defined subtypes of AML.

Eleanor Hilgart, Weiqiang Zhou, Eduardo Martinez-Montes, Adrian Idrizi, Rakel Tryggvadottir, Lukasz P Gondek, Ravindra Majeti, Hongkai Ji, Michael A Koldobskiy, Andrew P Feinberg.

Disruption of the epigenetic landscape is of particular interest in acute myeloid leukemia (AML) due to its relatively low mutational burden and frequent occurrence of mutations in epigenetic regulators. Here, we applied an information-theoretic analysis of methylation potential energy landscapes, capturing changes in mean methylation level and methylation entropy, to comprehensively analyze DNA methylation stochasticity in subtypes of AML defined by mutually exclusive genetic mutations. We identified AML subtypes with CEBPA double mutation and those with IDH mutations as distinctly high-entropy subtypes, marked by methylation disruption over a convergent set of genes. We found a core program of epigenetic landscape disruption across all AML subtypes, with discordant methylation stochasticity and transcriptional dysregulation converging on functionally important leukemic signatures, suggesting a genotype-independent role of stochastic disruption of the epigenetic landscape in mediating leukemogenesis. We further established a relationship between methylation entropy and gene expression variability, connecting the disruption of the epigenetic landscape to transcription in AML. This approach identified a convergent program of epigenetic dysregulation in leukemia, clarifying the contribution of specific genetic mutations to stochastic disruption of the epigenetic and transcriptional landscapes of AML.

DOI: https://doi.org/10.1101/2024.10.26.620422