bims-medica 2024-10-06 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–10–06
twenty-two papers selected by
Brett Chrest, Wake Forest University

Fructose shields human colorectal cancer cells from hypoxia-induced necroptosis.
Identifying metabolic limitations in the tumor microenvironment.
The effects of the ketogenic diet on cancer treatment: a narrative review.
Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme.
Pancreatic cancer tumor organoids exhibit subtype-specific differences in metabolic profiles.
Systematic Review and Clinical Insights: The Role of the Ketogenic Diet in Managing Glioblastoma in Cancer Neuroscience.
AMPK Activation in TET2 Downregulated Leukemia Cells Upon Glutamine Limitation.
Stable Isotope Tracing Experiments Using LC-MS.
Bridging the gap: advancing cancer cell culture to reveal key metabolic targets.
Mimicking and analyzing the tumor microenvironment.
Nutrition and Selected Lifestyle Elements as a Tertiary Prevention in Colorectal Cancer Patients.
Simultaneous assessment of NAD(P)H and flavins with multispectral fluorescence lifetime imaging microscopy at a single excitation wavelength of 750 nm.
Asparagine as a Signal for Glutamine Sufficiency via Asparagine Synthetase: A Fresh Evidence-Based Framework in Physiology and Oncology.
Sex differences in the molecular profile of adult diffuse glioma are shaped by IDH status and tumor microenvironment.
Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.
Dietary Counseling Interventions During Radiation Therapy: A Systematic Review of Feasibility, Safety, and Efficacy.
De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases.
Quantification of Total Ketone Bodies in Biological Matrices Using Stable Isotope-Labeled Internal Standards and RP-UHPLC-MS/MS.
Obesity Promotes the Ceramide-Mediated NADPH Oxidase in Acute Myeloid Leukemia.
Association between dietary factors and breast cancer risk: a matched case-control study in Vietnam.
Association between empirically derived nutrient patterns and breast cancer: a case-control study in a Middle Eastern country.
Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.

NPJ Sci Food. 2024 Oct 01. 8(1): 71

Fructose shields human colorectal cancer cells from hypoxia-induced necroptosis.

Xiang-Han Huang, Ching-Ying Huang.

Recent studies have shown that high dietary fructose intake enhances intestinal tumor growth in mice. Our previous work indicated that glucose enables hypoxic colorectal cancer (CRC) cells to resist receptor-interacting protein (RIP)-dependent necroptosis. Despite having the same chemical formula, glucose and fructose are absorbed through different transporters yet both can enter the glycolytic metabolic pathway. The excessive intake of dietary fructose, leading to its overflow into the colon, allows colonic cells to absorb fructose apically. This study explores the mechanisms behind apical fructose-mediated death resistance in CRC cells under hypoxic stress. Utilizing three CRC cell lines (Caco-2, HT29, and T84) under normoxic and hypoxic conditions with varying fructose concentrations, we assessed lactate dehydrogenase (LDH) activity, RIP1/3 complex formation (a necroptosis marker), and cell integrity. We investigated the role of fructose in glycolytic-mediated death resistance using glycolytic inhibitors iodoacetate (IA, a glycolytic inhibitor to glyceraldehyde 3-phosphate dehydrogenase), and UK5099 (UK, an inhibitor to mitochondrial pyruvate carrier). Our findings reveal that apical fructose prevents the hypoxia-induced RIP-dependent necroptosis in Caco-2 and HT29 cells. Fructose exposure under hypoxia also preserved epithelial integrity. IA, but not UK, blocked fructose-mediated glycolytic metabolite production and necrosis, indicating that anaerobic glycolytic metabolites facilitate death resistance. Notably, fructose treatment upregulated pyruvate kinase (PK)-M1 mRNA in hypoxic Caco-2 and HT29 cells, while PKM2 upregulation was exclusive to HT29 cells. In conclusion, apical fructose utilization through glycolysis effectively inhibits hypoxia-induced RIP-dependent necroptosis in CRC cells, shedding light on potential metabolic adaptation mechanisms in the tumor microenvironment and suggesting novel targets for therapeutic intervention.

DOI: https://doi.org/10.1038/s41538-024-00318-2
Sci Adv. 2024 Oct 04. 10(40): eadq7305

Identifying metabolic limitations in the tumor microenvironment.

Guillaume Cognet, Alexander Muir.

Solid tumors are characterized by dysfunctional vasculature that limits perfusion and delivery of nutrients to the tumor microenvironment. Limited perfusion coupled with the high metabolic demand of growing tumors has led to the hypothesis that many tumors experience metabolic stress driven by limited availability of nutrients such as glucose, oxygen, and amino acids in the tumor. Such metabolic stress has important implications for the biology of cells in the microenvironment, affecting both disease progression and response to therapies. Recently, techniques have been developed to identify limiting nutrients and resulting metabolic stresses in solid tumors. These techniques have greatly expanded our understanding of the metabolic limitations in tumors. This review will discuss these experimental tools and the emerging picture of metabolic limitations in tumors arising from recent studies using these approaches.

DOI: https://doi.org/10.1126/sciadv.adq7305
Eur J Cancer Prev. 2024 Sep 20.

The effects of the ketogenic diet on cancer treatment: a narrative review.

Qingxuan Deng, Ruyue Lv, Tangbin Zou.

Despite significant advances in therapy, cancer remains the top cause of death in parts of the globe. For many types of cancer, the typical treatment is a combination of surgery, chemotherapy, and radiotherapy. However, this conventional treatment is not successful on its own. As a consequence, innovative approaches that improve treatment efficacy are urgently needed. The ketogenic diet is a high-fat, moderate protein, and low-carbohydrate diet that appears to sensitize most cancers to conventional therapies by exploiting cancer cells' altered metabolism, making it an effective adjuvant cancer treatment alternative. This diet could decrease glucose metabolism while enhancing lipid metabolism, interfering with the Warburg effect, and inhibiting tumor cell proliferation. The anticancer impact of ketogenic diet has been established in numerous animal trials and clinical investigations on a wide range of tumor types, including glioblastoma, pancreatic cancer, head and neck cancer, breast cancer, invasive rectal cancer, ovarian cancer, and endometrial cancer. In this review, we discussed the various types of ketogenic diets, the mechanism of action for ketogenic diet as a cancer therapy, and the data gathered from continuing preclinical and clinical studies, intending to establish a solid theoretical foundation for future research.

DOI: https://doi.org/10.1097/CEJ.0000000000000918
Biomedicines. 2024 Sep 09. pii: 2050. [Epub ahead of print]12(9):

Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme.

María J Esteban-Amo, Patricia Jiménez-Cuadrado, Pablo Serrano-Lorenzo, Miguel Á de la Fuente, María Simarro.

  Succinate dehydrogenase (also known as complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Owing to the privileged position of SDH/CII, its dysfunction leads to TCA cycle arrest and altered respiration. This review aims to elucidate the widely documented profound metabolic effects of SDH/CII deficiency, along with the newly unveiled survival mechanisms in SDH/CII-deficient cells. Such an understanding reveals exploitable vulnerabilities for strategic targeting, which is crucial for the development of novel and more precise therapies for primary mitochondrial diseases, as well as for familial and sporadic cancers associated with SDH/CII mutations.

Keywords:  complex II; disease; mitochondria; succinate dehydrogenase

DOI:  https://doi.org/10.3390/biomedicines12092050
Cancer Metab. 2024 Oct 03. 12(1): 28

Pancreatic cancer tumor organoids exhibit subtype-specific differences in metabolic profiles.

Hassan A Ali, Joanna M Karasinska, James T Topham, Danisha Johal, Steve Kalloger, Andrew Metcalfe, Cassia S Warren, Anthony Miyagi, Lan V Tao, Maya Kevorkova, Shawn C Chafe, Paul C McDonald, Shoukat Dedhar, Seth J Parker, Daniel J Renouf, David F Schaeffer.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease characterized by complex metabolic rewiring that enables growth in changing nutrient availability and oxygen conditions. Transcriptome-based prognostic PDAC tumor subtypes, known as 'basal-like' and 'classical' subtypes are associated with differences in metabolic gene expression including genes involved in glycolysis. Tumor subtype-specific metabolism phenotypes may provide new targets for treatment development in PDAC, but their functional relevance has not been fully elucidated. We aimed to investigate differences in metabolic profiles and transcriptomes in tumor models derived from patients with basal-like and classical tumors.
METHODS: Patient-derived organoids (PDOs) were established from tumor biopsies collected from patients with metastatic PDAC, including three PDOs from basal-like and five PDOs from classical tumors. Metabolic analyses included assessment of differences in metabolic activity using Seahorse Glycolysis and Mito Stress tests and 13C-glucose metabolites tracing analysis. In order to investigate the influence of mitochondrial pyruvate transport on metabolic differences, PDOs were treated with the mitochondrial pyruvate carrier 1 (MPC1) inhibitor UK-5099. Prognostic relevance of MPC1 was determined using a tumor tissue microarray (TMA) in resectable, and proteomics profiling in metastatic PDAC datasets. Whole genome and transcriptome sequencing, differential gene expression and gene set enrichment analyses were performed in PDOs.
RESULTS: Metastatic PDAC PDOs showed subtype-specific differences in glycolysis and oxidative phosphorylation (OXPHOS). Basal-like tumor-derived PDOs had a lower baseline extracellular acidification rate, but higher glycolytic reserves and oxygen consumption rate (OCR) than classical tumor-derived PDOs. OCR difference was eliminated following treatment with UK-5099. In the 13C-glucose metabolites tracing experiment, a basal-like tumor PDO showed lower fractions of some M + 2 metabolites but higher sensitivity to UK-5099 mediated reduction in M + 2 metabolites than a classical tumor PDO. Protein level analyses revealed lower MPC1 protein levels in basal-like PDAC cases and association of low MPC1 levels with clinicopathologic parameters of tumor aggressiveness in PDAC. PDO differential gene expression analyses identified additional subtype-specific cellular pathways and potential disease outcome biomarkers.
CONCLUSIONS: Our findings point to distinct metabolic profiles in PDAC subtypes with basal-like tumor PDOs showing higher OXPHOS and sensitivity to MPC1 inhibition. Subtypes-specific metabolic vulnerabilities may be exploited for selective therapeutic targeting.

Keywords:  Glycolysis; MPC1; Metabolic profiling; OXPHOS; Organoids; PDAC; PDAC tumor subtype

DOI:  https://doi.org/10.1186/s40170-024-00357-z
J Pers Med. 2024 Aug 31. pii: 929. [Epub ahead of print]14(9):

Systematic Review and Clinical Insights: The Role of the Ketogenic Diet in Managing Glioblastoma in Cancer Neuroscience.

Jose Valerio, Matteo Borro, Elisa Proietti, Livia Pisciotta, Immanuel O Olarinde, Maria Fernandez Gomez, Andres Mauricio Alvarez Pinzon.

  Recent scientific research has shown that the ketogenic diet may have potential benefits in a variety of medical fields, which has led to the diet receiving a substantial amount of attention. Clinical and experimental research on brain tumors has shown that the ketogenic diet has a satisfactory safety profile. This safety profile has been established in a variety of applications, including the management of obesity and the treatment of drug-resistant epileptic cases. However, in human studies, the impact of ketogenic therapy on the growth of tumors and the life expectancy of patients has not provided results that are well characterized. Consequently, our purpose is to improve the comprehension of these features by succinctly presenting the developments and conclusions that have been gained from the most recent study that pertains to this non-pharmacological technique. According to the findings of our study, patients with brain tumors who stick to a ketogenic diet are more likely to experience improved survival rates. However, it is required to conduct additional research on humans in order to more accurately define the anti-tumor efficiency of this diet as well as the underlying processes that support the therapeutic effects of this dieting regimen.

Keywords:  fasting; glioma; ketogenic diet; ketosis

DOI:  https://doi.org/10.3390/jpm14090929
Medeni Med J. 2024 Sep 30. 39(3): 161-168

AMPK Activation in TET2 Downregulated Leukemia Cells Upon Glutamine Limitation.

Ahsen Merve Bayrak, Burcu Yucel.

   Objective: Metabolic rewiring is a characteristic of cancer cells. Cancer cells require more nutrients for survival and proliferation. Although glutamine can be produced in cells via a series of enzymatic reactions, a group of cancer cells are dependent on extracellular glutamine for survival. TET2 plays a role in DNA demethylation and is a tumor suppressor gene. The TET2 gene is frequently mutated in various cancers, including acute myeloid leukemia (AML). Our study aimed to investigate the association between TET2-knockdown AML cell line HL-60 cells and glutamine metabolism.
Methods: To evaluate the association between TET2 expression and glutamine limitation, TET2 was downregulated in HL-60 cells using shRNA plasmids. The proliferation of TET2-knockdown HL-60 cells was calculated in normal and glutamine-deficient medium. GLUL mRNA expression was investigated using quantitative reverse transcription polymerase chain reaction and protein levels were evaluated using immunoblotting.
Results: The numbers and viability of TET2-knockdown HL-60 cells were decreased in low glutamine-containing medium, but the viability of TET2-knockdown HL-60 cells was higher than that of control cells. GLUL mRNA expressions were increased in TET2-knockdown cells in low glutamine. In addition, P-AMPKα protein expression was increased in TET2-knockdown HL-60 cells in low glutamine-containing medium.
Conclusions: Our findings indicate that TET2-knockdown HL-60 cells may be more resistant to glutamine deprivation. In glutamine-deficient medium, the mRNA expression of glutamine synthetase is increased, which could be related to glutamine addiction in cells. In addition, low-glutamyl medium increased the P-AMPKα protein level in TET2-knockdown HL-60 cells.

Keywords:  AML; AMPK; Glutamine metabolism; TET2 expression; shRNA-mediated gene silencing

DOI:  https://doi.org/10.4274/MMJ.galenos.2024.59683
Methods Mol Biol. 2025 ;2855 103-116

Stable Isotope Tracing Experiments Using LC-MS.

Esther A Zaal, Jeroen W A Jansen, Celia R Berkers.

  Metabolomics has emerged as a pivotal field in understanding cellular function, particularly in the context of disease. In numerous diseases, including cancer, alterations in metabolism play an essential role in disease progression and drug response. Hence, unraveling the metabolic rewiring is of importance to find novel diagnostic and therapeutic strategies. Isotope tracing is a powerful technique for delving deeper into the metabolic wiring of cells. By tracking an isotopically labeled substrate through biochemical reactions in the cell, this technique provides a dynamic understanding of cellular metabolism. This chapter outlines a robust isotope tracing protocol utilizing high-resolution mass spectrometry coupled to liquid chromatography in cell culture-based models. We cover essential aspects of experimental design and analyses, providing a valuable resource for researchers aiming to employ isotopic tracing.

Keywords:  Fluxomics; High-performance liquid chromatography; Isotope tracing; Mass spectrometry; Metabolomics

DOI:  https://doi.org/10.1007/978-1-0716-4116-3_6
Front Oncol. 2024 ;14 1480613

Bridging the gap: advancing cancer cell culture to reveal key metabolic targets.

Marjolein M G Kes, Celia R Berkers, Jarno Drost.

  Metabolic rewiring is a defining characteristic of cancer cells, driving their ability to proliferate. Leveraging these metabolic vulnerabilities for therapeutic purposes has a long and impactful history, with the advent of antimetabolites marking a significant breakthrough in cancer treatment. Despite this, only a few in vitro metabolic discoveries have been successfully translated into effective clinical therapies. This limited translatability is partially due to the use of simplistic in vitro models that do not accurately reflect the tumor microenvironment. This Review examines the effects of current cell culture practices on cancer cell metabolism and highlights recent advancements in establishing more physiologically relevant in vitro culture conditions and technologies, such as organoids. Applying these improvements may bridge the gap between in vitro and in vivo findings, facilitating the development of innovative metabolic therapies for cancer.

Keywords:  cancer metabolism; cell culture conditions; organoids; oxygen; pH; physiologic media; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2024.1480613
Cell Rep Methods. 2024 Sep 25. pii: S2667-2375(24)00244-3. [Epub ahead of print] 100866

Mimicking and analyzing the tumor microenvironment.

Roxane Crouigneau, Yan-Fang Li, Jamie Auxillos, Eliana Goncalves-Alves, Rodolphe Marie, Albin Sandelin, Stine Falsig Pedersen.

  The tumor microenvironment (TME) is increasingly appreciated to play a decisive role in cancer development and response to therapy in all solid tumors. Hypoxia, acidosis, high interstitial pressure, nutrient-poor conditions, and high cellular heterogeneity of the TME arise from interactions between cancer cells and their environment. These properties, in turn, play key roles in the aggressiveness and therapy resistance of the disease, through complex reciprocal interactions between the cancer cell genotype and phenotype, and the physicochemical and cellular environment. Understanding this complexity requires the combination of sophisticated cancer models and high-resolution analysis tools. Models must allow both control and analysis of cellular and acellular TME properties, and analyses must be able to capture the complexity at high depth and spatial resolution. Here, we review the advantages and limitations of key models and methods in order to guide further TME research and outline future challenges.

Keywords:  CP: Biotechnology; CP: Cancer biology; cancer; heterogeneity; metabolism; microfluidics; organoids; tumor microenvironment; tumor models

DOI:  https://doi.org/10.1016/j.crmeth.2024.100866
Nutrients. 2024 Sep 16. pii: 3129. [Epub ahead of print]16(18):

Nutrition and Selected Lifestyle Elements as a Tertiary Prevention in Colorectal Cancer Patients.

Kamil Michał Mąkosza, Małgorzata Muc-Wierzgoń, Sylwia Dzięgielewska-Gęsiak.

   BACKGROUND: Nutrition and lifestyle elements can significantly support the therapeutic process in colorectal cancer (CRC) patients, which is the basis for tertiary prevention. The study aimed to assess the nutritional strategies and lifestyle of CRC patients and to determine differences in these behaviors depending on gender and age.
METHODS: The study group included 202 CRC patients. The research was carried out in two hospitals and using the snowball method. The research tool was an original questionnaire. Data were processed in statistical programs. p < 0.05 was considered statistically significant.
RESULTS: Patients reported many behavioral-nutritional side effects. Half of them did not use a therapeutic diet (n = 101; 50.0%). The majority of patients declared that they ate three meals a day (57.4%). Fruits and vegetables were mainly eaten raw (69.3%). Almost a quarter of patients were not physically active at all (22.3%). Men chose to fry meat significantly more often than women (27.7% vs. 19.3%) (p = 0.003). The elderly consumed fast food significantly less often than middle-aged (88.5% vs. 72.3%) (p = 0.03).
CONCLUSIONS: Patients showed both pro- and anti-health activities. The findings revealed several noteworthy disparities in dietary habits and lifestyle choices based on gender and age, indicating that these factors can significantly influence the health management of CRC patients. The patients' behaviors should be constantly monitored and intensified, especially through regular consultations and educational meetings with an oncology dietitian for nutritional tertiary prevention of chronic disease.

Keywords:  colorectal cancer patients; nutrition; selected lifestyle elements; tertiary prevention

DOI:  https://doi.org/10.3390/nu16183129
J Biomed Opt. 2024 Oct;29(10): 106501

Simultaneous assessment of NAD(P)H and flavins with multispectral fluorescence lifetime imaging microscopy at a single excitation wavelength of 750 nm.

Boris Yakimov, Anastasia Komarova, Elena Nikonova, Artem Mozherov, Liubov Shimolina, Marina Shirmanova, Wolfgang Becker, Evgeny Shirshin, Vladislav Shcheslavskiy.

   Significance: Autofluorescence characteristics of the reduced nicotinamide adenine dinucleotide and oxidized flavin cofactors are important for the evaluation of the metabolic status of the cells. The approaches that involve a detailed analysis of both spectral and time characteristics of the autofluorescence signals may provide additional insights into the biochemical processes in the cells and biological tissues and facilitate the transition of spectral fluorescence lifetime imaging into clinical applications.
Aim: We present the experiments on multispectral fluorescence lifetime imaging with a detailed analysis of the fluorescence decays and spectral profiles of the reduced nicotinamide adenine dinucleotide and oxidized flavin under a single excitation wavelength aimed at understanding whether the use of multispectral detection is helpful for metabolic imaging of cancer cells.
Approach: We use two-photon spectral fluorescence lifetime imaging microscopy. Starting from model solutions, we switched to cell cultures treated by metabolic inhibitors and then studied the metabolism of cells within tumor spheroids.
Results: The use of a multispectral detector in combination with an excitation at a single wavelength of 750 nm allows the identification of fluorescence signals from three components: free and bound NAD(P)H, and flavins based on the global fitting procedure. Multispectral data make it possible to assess not only the lifetime but also the spectral shifts of emission of flavins caused by chemical perturbations. Altogether, the informative parameters of the developed approach are the ratio of free and bound NAD(P)H amplitudes, the decay time of bound NAD(P)H, the amplitude of flavin fluorescence signal, the fluorescence decay time of flavins, and the spectral shift of the emission signal of flavins. Hence, with multispectral fluorescence lifetime imaging, we get five independent parameters, of which three are related to flavins.
Conclusions: The approach to probe the metabolic state of cells in culture and spheroids using excitation at a single wavelength of 750 nm and a fluorescence time-resolved spectral detection with the consequent global analysis of the data not only simplifies image acquisition protocol but also allows to disentangle the impacts of free and bound NAD(P)H, and flavin components evaluate changes in their fluorescence parameters (emission spectra and fluorescence lifetime) upon treating cells with metabolic inhibitors and sense metabolic heterogeneity within 3D tumor spheroids.

Keywords:  NAD(P)H; flavins; fluorescence lifetime imaging; metabolism; microscopy; time-correlated single photon counting

DOI:  https://doi.org/10.1117/1.JBO.29.10.106501
Am J Physiol Cell Physiol. 2024 Sep 30.

Asparagine as a Signal for Glutamine Sufficiency via Asparagine Synthetase: A Fresh Evidence-Based Framework in Physiology and Oncology.

Babatunde Olawuni, Barrie P Bode.

  Among the twenty proteinogenic amino acids, glutamine and asparagine represent a unique cohort in containing a terminal amide in their side chain, and share a direct metabolic relationship, with glutamine generating asparagine through the ATP-dependent asparagine synthetase (ASNS) reaction. Circulating glutamine levels and metabolic flux through cells and tissues greatly exceed those for asparagine, and "glutamine addiction" in cancer has likewise received considerable attention. However, historic and recent evidence collectively suggest that in spite of its modest presence, asparagine plays an outsized regulatory role in cellular function. Here, we present a unifying evidence-based hypothesis that the amides constitute a regulatory signaling circuit, with glutamine as a driver and asparagine as a second messenger that allosterically regulates key biochemical and physiological functions, particularly cell growth and survival. Specifically, it is proposed that ASNS serves as a sensor of substrate sufficiency for S-phase entry and progression in proliferating cells. ASNS-generated asparagine serves as a subsequent second messenger that modulates the activity of key regulatory proteins and promotes survival in the face of cellular stress, and serves as a feed-forward driver of S-phase progression in cell growth. We propose that this signaling pathway be termed the Amide Signaling Circuit (ASC) in homage to the SLC1A5-encoded ASCT2 that transports both glutamine and asparagine in a bidirectional manner, and has been implicated in the pathogenesis of a broad spectrum of human cancers. Support for the ASC model is provided by the recent discovery that glutamine is sensed in primary cilia via ASNS during metabolic stress.

Keywords:  Asparagine; Cancer; Glutamine; Metabolism; Signaling

DOI:  https://doi.org/10.1152/ajpcell.00316.2024
Neuro Oncol. 2024 Oct 05. pii: noae207. [Epub ahead of print]

Sex differences in the molecular profile of adult diffuse glioma are shaped by IDH status and tumor microenvironment.

Yingbo Huang, Yuting Shan, Weijie Zhang, Christina Printzis, Lorenzo Pesce, Danielle Maeser, Catherine Stanhope, Barbara E Stranger, R Stephanie Huang.

   BACKGROUND: Sex differences in adult diffuse glioma (ADG) are well-established clinically, yet the underlying molecular mechanisms remain inadequately understood. Here, we aim to reveal molecular features and cellular compositions unique to each sex in ADG to comprehend the role of sex in disease etiology.
METHODS: We quantified sex differences in transcriptome of ADG using multiple independent glioma patient datasets. Next, we delved into the single-cell landscape to examine sex differences in gene expression and cellular composition. To explore how sex influences disease progression, we analyzed paired samples from primary and recurrent ADG cases, aiming to identify sex-specific differences in molecular and cellular features.
RESULTS: Our analysis revealed that mutations in isocitrate dehydrogenase (IDH) genes and the tumor microenvironment emerged as primary influencers of sex-differential molecular enrichments. In IDHwt tumors, genes in neuronal signaling pathway are found to be enriched in male tumors, while genes in hypoxia and inflammatory response pathways are enriched in female tumors. This pattern was reversed in IDHmut gliomas. We hypothesized that these distinctions could be attributed to heterogeneous cellular composition between sexes. Using single-cell data, we observed distinctive patterns of sex differences in cell states, cell composition and cell-cell interaction in IDHwt and IDHmut tumors separately. Further, by comparing molecular changes in paired primary and recurrent ADG samples, we identified sex-specific differences in molecular characteristics and cellular compositions of recurrent tumors.
CONCLUSION: Our results provide a comprehensive multi-level characterization of sex differences in ADG, such findings provide novel insights into glioma disease progression in each sex.

Keywords:  Adult diffuse Glioma; Glioblastoma; Sex differences

DOI:  https://doi.org/10.1093/neuonc/noae207
Cell Stem Cell. 2024 Sep 26. pii: S1934-5909(24)00322-9. [Epub ahead of print]

Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.

Guoqiang Han, Manman Cui, Pengbo Lu, Tiantian Zhang, Rong Yin, Jin Hu, Jihua Chai, Jing Wang, Kexin Gao, Weidong Liu, Shuxin Yao, Ziyan Cao, Yanbing Zheng, Wen Tian, Rongxia Guo, Min Shen, Zheming Liu, Weiming Li, Shanshan Zhao, Xiangpeng Lin, Yuhui Zhang, Kehan Song, Yan Sun, Fuling Zhou, Haojian Zhang.

  Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3' UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.

Keywords:  RREB1; SDHD; acute myeloid leukemia; leukemia stem cell; mitochondria; succinate; translation; venetoclax

DOI:  https://doi.org/10.1016/j.stem.2024.09.008
Nutr Cancer. 2024 Sep 28. 1-25

Dietary Counseling Interventions During Radiation Therapy: A Systematic Review of Feasibility, Safety, and Efficacy.

Alexie Oppermann, Shalet James, Mackenzie M Minotti, Kaitlin M Schotz, Martha E Francis, Ian R Kleckner, Melissa A L Vyfhuis, Matthew J Ferris, Brenton J Baguley, Amber S Kleckner.

Radiotherapy is a common cancer treatment, and concurrent nutritional interventions can maintain nutritional status and improve clinical and supportive care outcomes. However, optimal nutritional interventions during radiotherapy are not firmly established. Herein, we assessed the feasibility, safety, and efficacy of dietary counseling interventions without oral nutrition supplements on health outcomes in adults receiving radiotherapy for cancer in a systematic review. Prospective clinical trials that implemented nutritional counseling interventions during radiotherapy were identified from four databases from inception through December 2023. Feasibility, safety, and efficacy were extracted from 32 articles that described 23 randomized and 4 non-randomized clinical trials. The interventions included individualized nutritional counseling (n = 14 articles), nutritional counseling plus exercise (n = 4), and nutritional counseling focused on increasing or reducing intake of specific nutrients (n = 9). Trials targeted head and neck (n = 12), pelvic cancers (n = 14), and/or breast (n = 5) cancers. Control groups had variable designs and included general nutrition education and intervention as needed. Studies recruited 120 ± 104 participants (range 26-468). Interventions tended to be feasible regarding retention and attendance at sessions, though feasibility metrics varied among different interventions. Most interventions were safe with no studies reporting adverse events attributable to dietary intervention. Individualized dietary counseling interventions tended to lead to between-group differences favoring the intervention group in regard to improved nutritional status, maintenance or attenuation of loss of body mass, improved quality of life, and reduced radiation-induced toxicities. Diets that encouraged/discouraged specific nutrients tended to recruit patients receiving radiation to the pelvic area and resulted in positive or neutral effects on gastrointestinal symptoms. In conclusion, nutritional interventions appear to be feasible, safe, and effective during radiotherapy for various symptom outcomes.

DOI: https://doi.org/10.1080/01635581.2024.2406999
Cell Rep Med. 2024 Oct 03. pii: S2666-3791(24)00485-3. [Epub ahead of print] 101755

De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases.

Agata M Kieliszek, Daniel Mobilio, Blessing I Bassey-Archibong, Jarrod W Johnson, Mathew L Piotrowski, Elvin D de Araujo, Abootaleb Sedighi, Nikoo Aghaei, Laura Escudero, Patrick Ang, William D Gwynne, Cunjie Zhang, Andrew Quaile, Dillon McKenna, Minomi Subapanditha, Tomas Tokar, Muhammad Vaseem Shaikh, Kui Zhai, Shawn C Chafe, Patrick T Gunning, J Rafael Montenegro-Burke, Chitra Venugopal, Jakob Magolan, Sheila K Singh.

  Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis and the current standard of care is palliative. Targeting BM-initiating cells (BMICs) is a feasible strategy to treat BM, but druggable targets are limited. Here, we apply Connectivity Map analysis to lung-, breast-, and melanoma-pre-metastatic BMIC gene expression signatures and identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo GTP synthesis pathway, as a target for BM. We show that pharmacological and genetic perturbation of IMPDH attenuates BMIC proliferation in vitro and the formation of BM in vivo. Metabolomic analyses and CRISPR knockout studies confirm that de novo GTP synthesis is a potent metabolic vulnerability in BM. Overall, our work employs a phenotype-guided therapeutic strategy to uncover IMPDH as a relevant target for attenuating BM outgrowth, which may provide an alternative treatment strategy for patients who are otherwise limited to palliation.

Keywords:  GTP synthesis; IMPDH; brain metastases; cancer stem cells

DOI:  https://doi.org/10.1016/j.xcrm.2024.101755
Methods Mol Biol. 2025 ;2855 117-131

Quantification of Total Ketone Bodies in Biological Matrices Using Stable Isotope-Labeled Internal Standards and RP-UHPLC-MS/MS.

Eric D Queathem, Alisa B Nelson, Patrycja Puchalska.

  Acetoacetate (AcAc) and D-beta-hydroxybutyrate (D-βOHB), the two major ketone bodies found in circulation, are linked to multiple physiological and pathophysiological states. Therefore, analytical methodologies surrounding the quantification of total ketone body (TKB) concentrations in biological matrices are paramount. Traditional methods to quantify TKBs relied on indirect spectrophotometric assays with narrow dynamic ranges, which have been significantly improved upon by modern mass spectrometry (MS)-based approaches. However, the lack of stable isotope-labeled internal standards (ISs) for AcAc and the need to distinguish D-βOHB from its closely related structural and enantiomeric isomers pose significant obstacles. Here, we provide a protocol to synthesize and quantify a [13C] stable isotope-labeled IS for AcAc, which, in conjunction with a commercially available [2H] stable isotope-labeled IS for βOHB, allows TKBs to be measured across multiple biological matrices. This rapid (7 min) analysis employs reverse phase ultra-high performance liquid chromatography (RP-UHPLC) coupled to tandem MS (MS/MS) to distinguish βOHB from three structural isomers using parallel reaction monitoring (PRM), providing excellent specificity and selectivity. Finally, a method is provided that distinguishes D-βOHB from L-βOHB using a simple one-step derivatization to produce the corresponding diastereomers, which can be chromatographically resolved using the same rapid RP-UHPLC separation with new PRM transitions. In summary, this method provides a rigorous analytical pipeline for the analysis of TKBs in biological matrices via leveraging two authentic stable isotope-labeled ISs and RP-UHPLC-MS/MS.

Keywords:  Acetoacetate; D-β-hydroxybutyrate; Ketone bodies; L-β-hydroxybutyrate; Stable isotope-labeled internal standards; Tandem mass spectrometry; Ultra-high performance liquid chromatography

DOI:  https://doi.org/10.1007/978-1-0716-4116-3_7
J Blood Disord Malig. 2024 ;pii: JBDM-2-105. [Epub ahead of print]2(1):

Obesity Promotes the Ceramide-Mediated NADPH Oxidase in Acute Myeloid Leukemia.

Weiyuan Wang, Rachel J Sabol, Alexus M Day, Tamara G Hathorn, Maria N Clark, Sara E Connell, Elena A Mantis, Mariam Traore, Jacqueline M Siciliano, Emma J Arsenault, Noelle T Labrecque, Emily C Sullivan, Andrea L Cote, Paul T Toran, Brian M Barth.

Acute myeloid leukemia (AML) is a type of blood cancer of the myeloid cell lineage. Obesity is characterized by an increase in body weight that results in excessive fat accumulation. Obesity has been associated with an increased incidence of many cancers, including blood cancers. This study evaluated the role obesity in AML progression in a novel transgenic mouse model developed by crossing Flt3ITD mice with Lepob/ob mice. Leukemia burden was augmented in obese AML mice. In addition, it was determined that obesity upregulated the ceramide-mediated and ceramide-1-phosphate-mediated NADPH oxidase 2 (NOX2). Notably, increased oxidative pathways has been attributed to disease progression in AML. Taken together, this study demonstrates a direct link between obesity and the progression of AML in part by augmenting the ceramide mediated NOX2.

Keywords: Acid sphingomyelinase; Acute myeloid leukemia; Ceramide; Ceramide kinase; Ceramide-1-phosphate; NADPH oxidase 2; Obesity
BMC Cancer. 2024 Oct 03. 24(1): 1224

Association between dietary factors and breast cancer risk: a matched case-control study in Vietnam.

Tam M Do, Quynh H N Nguyen, Nguyen H D Le, Hien D Nguyen, An H T Phung, Thach S Tran, Tuan V Nguyen, Lan T Ho-Pham.

   BACKGROUND: The role of diet in breast cancer prevention is controversial and limited in low-middle-income countries (LMICs). This study aimed to investigate the association between different dietary factors and breast cancer risk in Vietnamese women.
METHODS: Three hundred seventy newly histologically confirmed breast cancer cases and 370 controls matched by 5-year age from September 2019 to March 2020 in Ho Chi Minh City were recorded dietary intake using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (95% CI) were evaluated using conditional logistic regression and adjusted with potential confounders.
RESULTS: Compared to the lowest quartile of intake, we found that the highest intake of vegetables, fruit, soybean products, coffee, and egg significantly decreased breast cancer risk, including dark green vegetables (OR 0.46, 95% CI 0.27-0.78, ptrend=0.022), legumes (OR 0.19, 95% CI 0.08-0.44, ptrend <0.001), starchy vegetables (OR 0.37, 95% CI 0.21-0.66, ptrend=0.003), other vegetables (OR 0.46, 95% CI 0.28-0.77, ptrend=0.106), fruits (OR 0.44, 95% CI 0.26-0.74, ptrend <0.001), soybean product (OR 0.45, 95% CI 0.24-0.86, ptrend=0.311), coffee (OR 0.47, 95% CI 0.23-0.95, ptrend 0.004), and egg (OR 0.4, 95% CI 0.23-0.71, ptrend=0.002).
CONCLUSION: Greater consumption of vegetables, fruit, soybean products, coffee, and eggs is associated with a lower risk of breast cancer. This study provides evidence of breast cancer prevention by increasing the intake of these dietary groups, especially in LMICs.

Keywords:  Breast cancer; Diet; Risk factor; Vietnam

DOI:  https://doi.org/10.1186/s12885-024-12918-y
BMC Nutr. 2024 Sep 27. 10(1): 124

Association between empirically derived nutrient patterns and breast cancer: a case-control study in a Middle Eastern country.

Farimah Dehghani, Bahareh Sasanfar, Fatemeh Toorang, Kazem Zendehdel, Amin Salehi-Abargouei.

   PURPOSE: The risk of breast cancer (BC) and related mortality have increased in Middle-East countries during recent decades. The relationship between several nutrient intakes and the risk of BC has been investigated in several studies. However, few studies have estimated the effects of patterns of different nutrient intake on the risk of BC in this region.
METHODS: A total of 453 patients who were recently diagnosed with breast cancer and 516 healthy women participated in the current case-control study. To evaluate the dietary intakes, we used a validated 168-item food frequency questionnaire (FFQ) during the last year. Nutrient Patterns (NPs) were extracted through factor analysis (FA) of energy-adjusted twenty-six nutrients. The relationship between nutrient patterns and the risk of breast cancer in pre and post-menopausal women was estimated by multivariable regression.
RESULTS: Four major nutrient patterns were identified in the current study. The first nutrient pattern was rich in animal protein, retinol, riboflavin, pantothenic acid, cobalamin, and calcium. Higher saturated fatty acids (SFAs), mono-unsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and trans fatty acids (TFAs), and lower intakes of niacin were observed in nutrient pattern 2. The third nutrient pattern was rich in fiber, potassium, and vitamin C. Nutrient pattern 4, was associated with higher intakes of vegetable protein, alpha-tocopherol, and magnesium. A significant inverse relationship was observed between adherence to nutrient pattern 3 and the risk of BC in all participants [odds ratio (OR) = 0.70, 95% confidence interval (CI): 0.50, 0.97, P = 0.03) and pre-menopausal women (OR = 0.59 (0.39-0.89), P = 0.01).
CONCLUSION: Decreasing odds of breast cancer were observed by adherence to a nutrient pattern high in dietary fiber, vitamin C, and potassium. Future prospective investigations are recommended to confirm these findings.

Keywords:  Breast cancer; Case–control; Middle-Eastern countries; Nutrient pattern

DOI:  https://doi.org/10.1186/s40795-024-00934-x
Cell Death Discov. 2024 Sep 30. 10(1): 417

Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.

Elisabet Cuyàs, Stefano Pedarra, Sara Verdura, Miguel Angel Pardo, Roderic Espin Garcia, Eila Serrano-Hervás, Àngela Llop-Hernández, Eduard Teixidor, Joaquim Bosch-Barrera, Eugeni López-Bonet, Begoña Martin-Castillo, Ruth Lupu, Miguel Angel Pujana, Josep Sardanyès, Tomás Alarcón, Javier A Menendez.

Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance. FASN expression negatively correlates with infiltrating immune cells associated with cancer suppression, cytolytic activity signatures, and HLA-I expression. Cancer cells engineered to carry a loss-of-function mutation in FASN exhibit an enhanced cytolytic response and an accelerated extinction kinetics upon interaction with cytokine-activated T cells. Depletion of FASN results in reduced carrying capacity, accompanied by the suppression of mitochondrial OXPHOS and strong downregulation of electron transport chain complexes. Targeted FASN depletion primes cancer cells for mitochondrial apoptosis as it synergizes with BCL-2/BCL-XL-targeting BH3 mimetics to render cancer cells more susceptible to T-cell-mediated killing. FASN depletion prevents adaptive induction of PD-L1 in response to interferon-gamma and reduces constitutive overexpression of PD-L1 by abolishing PD-L1 post-translational palmitoylation. FASN is a novel tumor cell-intrinsic metabolic checkpoint that restricts T cell immunity and may be exploited to improve the efficacy of T cell-based immunotherapy.

DOI: https://doi.org/10.1038/s41420-024-02184-z