bims-medica 2024-07-21 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒07‒21
seventeen papers selected by
Brett Chrest, East Carolina University

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
Robustness of mitochondrial biogenesis and respiration explain aerobic glycolysis.
Mitochondrial Proteins as Metabolic Biomarkers and Sites for Therapeutic Intervention in Primary and Metastatic Cancers.
Ketomimetic Medium Promotes Metastatic Disposition and Chemoresistance in Breast Cancer Cells through Hypersialylation and Lipid Synthesis.
Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: A randomized clinical trial.
Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.
Including glutamine in a resource allocation model of energy metabolism in cancer and yeast cells.
Dietary interventions and tumor response to chemotherapy in breast cancer: A comprehensive review of preclinical and clinical data.
Spatial Proteomic Profiling of Colorectal Cancer Revealed Its Tumor Microenvironment Heterogeneity.
Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia.
Brain responses to intermittent fasting and the healthy living diet in older adults.
Skeletal muscle p53-depletion uncovers a mechanism of fuel usage suppression that enables efficient energy conservation.
Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance.
The effect of BMI on survival outcome of breast cancer patients: a systematic review and meta-analysis.
Regulation of and challenges in targeting NAD+ metabolism.
Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.
Expression of the plasma membrane citrate carrier (pmCiC) in human cancerous tissues-correlation with tumour aggressiveness.

bioRxiv. 2024 Jul 11. pii: 2024.07.09.602593. [Epub ahead of print]

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.

Eric D Queathem, Zahra Moazzami, David B Stagg, Alisa B Nelson, Kyle Fulghum, Abdirahman Hayir, Alisha Seay, Jacob R Gillingham, D Andre d'Avignon, Xianlin Han, Hai-Bin Ruan, Peter A Crawford, Patrycja Puchalska.

Therapeutic interventions targeting hepatic lipid metabolism in metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) remain elusive. Using mass spectrometry-based stable isotope tracing and shotgun lipidomics, we established a novel link between ketogenesis and MASLD pathophysiology. Our findings show that mouse liver and primary hepatocytes consume ketone bodies to support fatty acid (FA) biosynthesis via both de novo lipogenesis (DNL) and FA elongation. Analysis of 13 C-labeled FAs in hepatocytes lacking mitochondrial D-β-hydroxybutyrate dehydrogenase (BDH1) revealed a partial reliance on mitochondrial conversion of D-βOHB to acetoacetate (AcAc) for cytoplasmic DNL contribution, whereas FA elongation from ketone bodies was fully dependent on cytosolic acetoacetyl-CoA synthetase (AACS). Ketone bodies were essential for polyunsaturated FA (PUFA) homeostasis in hepatocytes, as loss of AACS diminished both free and esterified PUFAs. Ketogenic insufficiency depleted liver PUFAs and increased triacylglycerols, mimicking human MASLD, suggesting that ketogenesis supports PUFA homeostasis, and may mitigate MASLD-MASH progression in humans.

DOI: https://doi.org/10.1101/2024.07.09.602593
bioRxiv. 2024 Jul 05. pii: 2024.07.04.601975. [Epub ahead of print]

Robustness of mitochondrial biogenesis and respiration explain aerobic glycolysis.

Easun Arunachalam, Felix C Keber, Richard C Law, Chirag K Kumar, Yihui Shen, Junyoung O Park, Martin Wühr, Daniel J Needleman.

A long-standing observation is that in fast-growing cells, respiration rate declines with increasing growth rate and is compensated by an increase in fermentation, despite respiration being more efficient than fermentation. This apparent preference for fermentation even in the presence of oxygen is known as aerobic glycolysis, and occurs in bacteria, yeast, and cancer cells. Considerable work has focused on understanding the potential benefits that might justify this seemingly wasteful metabolic strategy, but its mechanistic basis remains unclear. Here we show that aerobic glycolysis results from the saturation of mitochondrial respiration and the decoupling of mitochondrial biogenesis from the production of other cellular components. Respiration rate is insensitive to acute perturbations of cellular energetic demands or nutrient supplies, and is explained simply by the amount of mitochondria per cell. Mitochondria accumulate at a nearly constant rate across different growth conditions, resulting in mitochondrial amount being largely determined by cell division time. In contrast, glucose uptake rate is not saturated, and is accurately predicted by the abundances and affinities of glucose transporters. Combining these models of glucose uptake and respiration provides a quantitative, mechanistic explanation for aerobic glycolysis. The robustness of specific respiration rate and mitochondrial biogenesis, paired with the flexibility of other bioenergetic and biosynthetic fluxes, may play a broad role in shaping eukaryotic cell metabolism.

DOI: https://doi.org/10.1101/2024.07.04.601975
Mini Rev Med Chem. 2024 ;24(12): 1187-1202

Mitochondrial Proteins as Metabolic Biomarkers and Sites for Therapeutic Intervention in Primary and Metastatic Cancers.

Diana Xochiquetzal Robledo-Cadena, Silvia Cecilia Pacheco-Velazquez, Jorge Luis Vargas-Navarro, Joaquín Alberto Padilla-Flores, Rafael Moreno-Sanchez, Sara Rodríguez-Enríquez.

  Accelerated aerobic glycolysis is one of the main metabolic alterations in cancer, associated with malignancy and tumor growth. Although glycolysis is one of the most studied properties of tumor cells, recent studies demonstrate that oxidative phosphorylation (OxPhos) is the main ATP provider for the growth and development of cancer. In this last regard, the levels of mRNA and protein of OxPhos enzymes and transporters (including glutaminolysis, acetate and ketone bodies catabolism, free fatty acid β-oxidation, Krebs Cycle, respiratory chain, phosphorylating system- ATP synthase, ATP/ADP translocator, Pi carrier) are altered in tumors and cancer cells in comparison to healthy tissues and organs, and non-cancer cells. Both energy metabolism pathways are tightly regulated by transcriptional factors, oncogenes, and tumor-suppressor genes, all of which dictate their protein levels depending on the micro-environmental conditions and the type of cancer cell, favoring cancer cell adaptation and growth. In the present review paper, variation in the mRNA and protein levels as well as in the enzyme/ transporter activities of the OxPhos machinery is analyzed. An integral omics approach to mitochondrial energy metabolism pathways may allow for identifying their use as suitable, reliable biomarkers for early detection of cancer development and metastasis, and for envisioned novel, alternative therapies.

Keywords:  Metabolic biomarker; anti-mitochondrial therapy.; cancer mitochondria; mitochondrial proteins; oxidative phosphorylation

DOI:  https://doi.org/10.2174/0113895575254320231030051124
bioRxiv. 2024 Jul 05. pii: 2024.07.03.601966. [Epub ahead of print]

Ketomimetic Medium Promotes Metastatic Disposition and Chemoresistance in Breast Cancer Cells through Hypersialylation and Lipid Synthesis.

Mohini Kamra, Yuan-I Chen, Paula C Delgado, Erin Seeley, Stephanie K Seidlits, Hsin-Chin Yeh, Amy Brock, Sapun H Parekh.

Although metastasis accounts for the vast majority of cancer-related fatalities, the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown. Recent evidence suggests that a common feature of invasive and resistant cells could be their metabolic state. However, attempts to control metabolic state via nutrient intake, e.g., ketogenic or low carbohydrate diets, have shown inconsistent results with respect to improving chemotherapy efficacy and curbing metastasis. Aiming to decode the molecular mechanisms that alter cell phenotype upon nutrient alteration, we study how a ketomimetic (ketone body-rich, low glucose) medium affects Doxorubicin (DOX) susceptibility and invasive disposition of BC cells. We quantified glycocalyx sialylation and found an inverse correlation with DOX-induced cytotoxicity and DOX internalization. These measurements were coupled with single-cell metabolic imaging, bulk migration studies, and transcriptomic and metabolomic analyses to map the mechanisms involved in ketone body-driven BC cell metabolic maneuvering. Our findings revealed that a ketomimetic medium enhances chemoresistance and invasive disposition of BC cells via two main oncogenic pathways: hypersialylation and lipid accumulation. We propose that the crosstalk between these pathways leads to synthesis of the glycan precursor UDP-GlcNAc, which leads to advancement of a metastatic phenotype in BC cells under ketomimetic conditions.

DOI: https://doi.org/10.1101/2024.07.03.601966
Clin Nutr. 2024 Jul 05. pii: S0261-5614(24)00228-0. [Epub ahead of print]43(8): 1914-1928

Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: A randomized clinical trial.

Martha Guevara-Cruz, Karla G Hernández-Gómez, Citlally Condado-Huerta, Luis E González-Salazar, Ana Karen Peña-Flores, Edgar Pichardo-Ontiveros, Aurora E Serralde-Zúñiga, Mónica Sánchez-Tapia, Otoniel Maya, Isabel Medina-Vera, Lilia G Noriega, Adriana López-Barradas, Oscar Rodríguez-Lima, Irma Mata, Viridiana Olin-Sandoval, Nimbe Torres, Armando R Tovar, Laura A Velázquez-Villegas.

  BACKGROUND: Mitochondrial dysfunction occurs in monocytes during obesity and contributes to a low-grade inflammatory state; therefore, maintaining good mitochondrial conditions is a key aspect of maintaining health. Dietary interventions are primary strategies for treating obesity, but little is known about their impact on monocyte bioenergetics. Thus, the aim of this study was to evaluate the effects of calorie restriction (CR), intermittent fasting (IF), a ketogenic diet (KD), and an ad libitum habitual diet (AL) on mitochondrial function in monocytes and its modulation by the gut microbiota.METHODS AND FINDINGS: A randomized controlled clinical trial was conducted in which individuals with obesity were assigned to one of the 4 groups for 1 month. Subsequently, the subjects received rifaximin and continued with the assigned diet for another month. The oxygen consumption rate (OCR) was evaluated in isolated monocytes, as was the gut microbiota composition in feces and anthropometric and biochemical parameters. Forty-four subjects completed the study, and those who underwent CR, IF and KD interventions had an increase in the maximal respiration OCR (p = 0.025, n2p = 0.159 [0.05, 0.27] 95% confidence interval) in monocytes compared to that in the AL group. The improvement in mitochondrial function was associated with a decrease in monocyte dependence on glycolysis after the IF and KD interventions. Together, diet and rifaximin increased the gut microbiota diversity in the IF and KD groups (p = 0.0001), enriched the abundance of Phascolarctobacterium faecium (p = 0.019) in the CR group and Ruminococcus bromii (p = 0.020) in the CR and KD groups, and reduced the abundance of lipopolysaccharide (LPS)-producing bacteria after CR, IF and KD interventions compared to the AL group at the end of the study according to ANCOVA with covariate adjustment. Spearman's correlation between the variables measured highlighted LPS as a potential modulator of the observed effects. In line with this findings, serum LPS and intracellular signaling in monocytes decreased with the three interventions (CR, p = 0.002; IF, p = 0.001; and KD, p = 0.001) compared to those in the AL group at the end of the study.
CONCLUSIONS: We conclude that these dietary interventions positively regulate mitochondrial bioenergetic health and improve the metabolic profile of monocytes in individuals with obesity via modulation of the gut microbiota. Moreover, the evaluation of mitochondrial function in monocytes could be used as an indicator of metabolic and inflammatory status, with potential applications in future clinical trials.
TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05200468).

Keywords:  Dietary interventions; Gut microbiota; Mitochondrial function; Monocyte bioenergetics; Obesity

DOI:  https://doi.org/10.1016/j.clnu.2024.06.036
Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2319782121

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.

Daniel Maxim Iascone, Xue Zhang, Patricia Brafford, Clementina Mesaros, Yogev Sela, Samuel Hofbauer, Shirley L Zhang, Sukanya Madhwal, Kieona Cook, Pavel Pivarshev, Ben Z Stanger, Stewart Anderson, Chi V Dang, Amita Sehgal.

  Crosstalk between metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to disease. Here, we investigated whether maintenance of circadian rhythms depends on specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to signal from a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function across a series of pancreatic adenocarcinoma cell lines. Metabolic profiling of congenic tumor cell clones revealed substantial diversity among these lines that we used to identify clones to generate circadian reporter lines. We observed diverse circadian profiles among these lines that varied with their metabolic phenotype: The most hypometabolic line [exhibiting low levels of oxidative phosphorylation (OxPhos) and glycolysis] had the strongest rhythms, while the most hypermetabolic line had the weakest rhythms. Pharmacological enhancement of OxPhos decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, inhibition of OxPhos enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

Keywords:  adenocarcinoma; cancer; circadian rhythms; luciferase; metabolism

DOI:  https://doi.org/10.1073/pnas.2319782121
NPJ Syst Biol Appl. 2024 Jul 18. 10(1): 77

Including glutamine in a resource allocation model of energy metabolism in cancer and yeast cells.

Jan Ewald, Ziyang He, Wassili Dimitriew, Stefan Schuster.

Energy metabolism is crucial for all living cells, especially during fast growth or stress scenarios. Many cancer and activated immune cells (Warburg effect) or yeasts (Crabtree effect) mostly rely on aerobic glucose fermentation leading to lactate or ethanol, respectively, to generate ATP. In recent years, several mathematical models have been proposed to explain the Warburg effect on theoretical grounds. Besides glucose, glutamine is a very important substrate for eukaryotic cells-not only for biosynthesis, but also for energy metabolism. Here, we present a minimal constraint-based stoichiometric model for explaining both the classical Warburg effect and the experimentally observed respirofermentation of glutamine (WarburQ effect). We consider glucose and glutamine respiration as well as the respective fermentation pathways. Our resource allocation model calculates the ATP production rate, taking into account enzyme masses and, therefore, pathway costs. While our calculation predicts glucose fermentation to be a superior energy-generating pathway in human cells, different enzyme characteristics in yeasts reduce this advantage, in some cases to such an extent that glucose respiration is preferred. The latter is observed for the fungal pathogen Candida albicans, which is a known Crabtree-negative yeast. Further, optimization results show that glutamine is a valuable energy source and important substrate under glucose limitation, in addition to its role as a carbon and nitrogen source of biomass in eukaryotic cells. In conclusion, our model provides insights that glutamine is an underestimated fuel for eukaryotic cells during fast growth and infection scenarios and explains well the observed parallel respirofermentation of glucose and glutamine in several cell types.

DOI: https://doi.org/10.1038/s41540-024-00393-x
Clin Nutr ESPEN. 2024 Jul 01. pii: S2405-4577(24)00194-3. [Epub ahead of print]63 462-475

Dietary interventions and tumor response to chemotherapy in breast cancer: A comprehensive review of preclinical and clinical data.

Ifeoma J Dikeocha, Hannah R Wardill, Janet K Coller, Joanne M Bowen.

  BACKGROUND & AIMS: Optimizing treatment efficacy is still a critical part in advancing the treatment of breast cancer. Dietary interventions have drawn significant attention for their potential to increase tumor sensitivity, with a plethora of strategies evaluated both preclinically and clinically. The aim of this paper is to explore these strategies, ranging from entire dietary programs to specific supplements, for their potential to directly enhance tumor sensitivity and chemotherapy adherence.METHODS: PubMed, Scopus, Embase and Web of Science databases were searched up to September 2023. In this comprehensive review, preclinical and clinical research on dietary interventions used in conjunction with chemotherapy for breast cancer was examined and synthesized, to identify potential causal mechanisms.
RESULTS: 42 studies in total were identified and synthesized, 32 pre-clinical and 8 clinical studies.
CONCLUSION: Although a topic of intense interest, the heterogeneity in approaches has resulted in a large but minimally impactful evidence base, further complicated by a limited understanding of the mechanisms at play. This review highlights the areas for further research to increase opportunities for nutritional-based interventions as adjuvant to chemotherapy for breast cancer.

Keywords:  Breast cancer; Chemotherapy; Diet; Tumor response

DOI:  https://doi.org/10.1016/j.clnesp.2024.06.048
J Proteome Res. 2024 Jul 18.

Spatial Proteomic Profiling of Colorectal Cancer Revealed Its Tumor Microenvironment Heterogeneity.

Lifen Xie, Qian Kong, Meiling Ai, An He, Bin Yao, Luobin Zhang, Keren Zhang, Chaowei Zhu, Yangqiu Li, Ligang Xia, Ruijun Tian, Ruilian Xu.

  Colorectal cancer is a predominant malignancy with a second mortality worldwide. Despite its prevalence, therapeutic options remain constrained and surgical operation is still the most useful therapy. In this regard, a comprehensive spatially resolved quantitative proteome atlas was constructed to explore the functional proteomic landscape of colorectal cancer. This strategy integrates histopathological analysis, laser capture microdissection, and proteomics. Spatial proteome profiling of 200 tissue section samples facilitated by the fully integrated sample preparation technology SISPROT enabled the identification of more than 4000 proteins on the Orbitrap Exploris 240 from 2 mm2 × 10 μm tissue sections. Compared with normal adjacent tissues, we identified a spectrum of cancer-associated proteins and dysregulated pathways across various regions of colorectal cancer including ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. Additionally, we conducted proteomic analysis on tumoral epithelial cells and paracancerous epithelium from early to advanced stages in hallmark rectum cancer and sigmoid colon cancer. Bioinformatics analysis revealed functional proteins and cell-type signatures associated with different regions of colorectal tumors, suggesting potential clinical implications. Overall, this study provides a comprehensive spatially resolved functional proteome landscape of colorectal cancer, serving as a valuable resource for exploring potential biomarkers and therapeutic targets.

Keywords:  cell type; colorectal cancer; heterogeneity; proteomics; spatial resolution

DOI:  https://doi.org/10.1021/acs.jproteome.3c00719
Cancer Res. 2024 Jul 18.

Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia.

Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh V Dharia, Ashleigh Meyer, Lucy A Merickel, Delan Khalid, Sebastian Scheich, Bjorn Haupl, Louis M Staudt, Thomas Oellerich, Kimberly Stegmaier.

Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships, and gene expression in cancer models. Here, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the beta subunit of the sodium-potassium pump (Na/K-ATP pump), interacts with the alpha subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3's paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells both through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. ATP1B3 is thus a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3560
Cell Metab. 2024 Jul 16. pii: S1550-4131(24)00283-3. [Epub ahead of print]

Brain responses to intermittent fasting and the healthy living diet in older adults.

Dimitrios Kapogiannis, Apostolos Manolopoulos, Roger Mullins, Konstantinos Avgerinos, Francheska Delgado-Peraza, Maja Mustapic, Carlos Nogueras-Ortiz, Pamela J Yao, Krishna A Pucha, Janet Brooks, Qinghua Chen, Shalaila S Haas, Ruiyang Ge, Lisa M Hartnell, Mark R Cookson, Josephine M Egan, Sophia Frangou, Mark P Mattson.

DOI: https://doi.org/10.1016/j.cmet.2024.07.012
J Cachexia Sarcopenia Muscle. 2024 Jul 15.

Skeletal muscle p53-depletion uncovers a mechanism of fuel usage suppression that enables efficient energy conservation.

Georgia Lenihan-Geels, Francisco Garcia Carrizo, Marina Leer, Sabrina Gohlke, Moritz Oster, Sophie Pöhle-Kronawitter, Christiane Ott, Alexandra Chadt, Isabel N Reinisch, Markus Galhuber, Chen Li, Wenke Jonas, Markus Jähnert, Susanne Klaus, Hadi Al-Hasani, Tilman Grune, Annette Schürmann, Tobias Madl, Andreas Prokesch, Michael Schupp, Tim J Schulz.

  BACKGROUND: The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability.METHODS: A mouse model with inducible deletion of the p53-encoding gene, Trp53, in skeletal muscle was generated using the Cre-loxP-system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice.
RESULTS: Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (-62,0%; P < 0.0001 and -52.7%; P < 0.0001, respectively). This was accompanied by changes in marker gene expression patterns of circadian rhythmicity and hyperactivity (+57.4%; P = 0.0068). These metabolic changes occurred acutely, within 2-3 days after deletion of Trp53 was initiated, suggesting a rapid adaptive response to loss of p53, which resulted in a transient increase in lactate release to the circulation (+46.6%; P = 0.0115) from non-exercised muscle as a result of elevated carbohydrate mobilization. Conversely, an impairment of proteostasis and amino acid metabolism was observed in knockout mice during fasting. During endurance exercise testing, mice with acute, muscle-specific Trp53 inactivation displayed an early exhaustion phenotype with a premature shift in fuel usage and reductions in multiple performance parameters, including a significantly reduced running time and distance (-13.8%; P = 0.049 and -22.2%; P = 0.0384, respectively).
CONCLUSIONS: These findings suggest that efficient nutrient conservation is a key element of normal metabolic homeostasis that is sustained by p53. The homeostatic state in metabolic tissues is actively maintained to coordinate efficient energy conservation and metabolic flexibility towards nutrient stress. The acute deletion of Trp53 unlocks mechanisms that suppress the activity of nutrient catabolic pathways, causing substantial loss of intramuscular energy stores, which contributes to a fasting-like state in muscle tissue. Altogether, these findings uncover a novel function of p53 in the short-term regulation of nutrient metabolism in skeletal muscle and show that p53 serves to maintain metabolic homeostasis and efficient energy conservation.

Keywords:  Energy conservation; Metabolic efficiency; Metabolic homeostasis; Metabolism; Skeletal muscle; p53

DOI:  https://doi.org/10.1002/jcsm.13529
bioRxiv. 2024 Jul 02. pii: 2024.06.30.601416. [Epub ahead of print]

Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance.

Ryan H Boe, Catherine G Triandafillou, Rossana Lazcano, Jennifer A Wargo, Arjun Raj.

Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, in vitro, these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment. Through spatial transcriptomics and single-cell RNA sequencing, we uncovered distinct resistance programs in melanoma cells shaped by both intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization revealed shared intrinsic resistance programs across different cell lines, highlighting the presence of universal and unique resistance pathways. In patient samples, we demonstrated that these resistance programs coexist within individual tumors and associate with diverse immune signatures, suggesting that the tumor microenvironment and distribution of resistant fates are closely connected. Single-cell resolution spatial transcriptomics in xenograft models revealed both intrinsically determined and extrinsically influenced resistant fates. Overall, this work demonstrates that each therapy resistant fate coexists with a distinct immune microenvironment in tumors and that, in vivo, tissue features, such as regions of necrosis, can influence which resistant fate is adopted.

DOI: https://doi.org/10.1101/2024.06.30.601416
Clin Transl Oncol. 2024 Jul 16.

The effect of BMI on survival outcome of breast cancer patients: a systematic review and meta-analysis.

Yu-Huan Kong, Jing-Yi Huang, Ye Ding, Shu-Hua Chen, Qiu-Shuang Li, Yang Xiong.

  OBJECTIVE: The main goal of the present research is to explore the potential link of body mass index (BMI) with different survival metrics in breast cancer patients. Our aim is to offer the latest and most thorough meta-analysis, assessing the strength and reliability of the connection that BMI has with prognostic indicators in this disease.PATIENTS AND METHODS: As of January 2024, we conducted a systematic literature search across PubMed, Embase, Web of Science, and the Cochrane Library databases. Our search aimed to identify studies examining BMI as an exposure factor, with breast cancer patients constituting the study population, and utilizing adjusted hazard ratio (HR) as the data type of interest.
RESULTS: The evidence synthesis incorporated a total of 61 eligible articles involving 201,006 patients. Being underweight posed a risk factor for overall survival (OS) in breast cancer patients compared to normal weight (HR 1.15, 95% CI 0.98-1.35; P = 0.08). Overweight or obesity, in comparison to normal weight, was a risk factor for OS (HR 1.18, 95% CI 1.14-1.23; P < 0.00001), disease-free survival (DFS) (HR 1.11, 95% CI 1.08-1.13; P < 0.00001), relapse-free survival (RFS) (HR 1.14, 95% CI 1.06-1.22; P = 0.03), and breast cancer-specific survival (BCSS) (HR 1.18, 95% CI 1.11-1.26; P < 0.00001), but not for progression-free survival (PFS) (HR 0.91, 95% CI 0.76-1.10; P = 0.33). Notably, in subgroup analyses, overweight patients achieved prolonged PFS (HR 0.80, 95% CI 0.64-0.99; P = 0.04), and compared to the obese population, the overweight cohort exhibited a significant difference in OS (HR 1.11, 95% CI 1.05-1.16; P < 0.00001) and DFS (HR 1.06, 95% CI 1.03-1.10; P = 0.0004), with a considerably stronger association. Furthermore, compared to HER- patients, HER + patients exhibited a greater predictive value for OS (HR 1.23, 95% CI 1.10-1.37; P = 0.0004), RFS (HR 1.30, 95% CI 1.03-1.64; P < 0.00001), and DFS (HR 1.10, 95% CI 1.03-1.17; P = 0.003).
CONCLUSIONS: The results of our meta-analysis reveal a notable association between BMI and various survival measures in breast cancer prognosis. These findings provide a solid basis for predicting breast cancer outcomes and implementing more effective therapeutic approaches.

Keywords:  Body mass index; Breast cancer; Meta-analysis; Prognosis; Systematic review

DOI:  https://doi.org/10.1007/s12094-024-03563-9
Nat Rev Mol Cell Biol. 2024 Jul 18.

Regulation of and challenges in targeting NAD+ metabolism.

Marie E Migaud, Mathias Ziegler, Joseph A Baur.

Nicotinamide adenine dinucleotide, in its oxidized (NAD+) and reduced (NADH) forms, is a reduction-oxidation (redox) co-factor and substrate for signalling enzymes that have essential roles in metabolism. The recognition that NAD+ levels fall in response to stress and can be readily replenished through supplementation has fostered great interest in the potential benefits of increasing or restoring NAD+ levels in humans to prevent or delay diseases and degenerative processes. However, much about the biology of NAD+ and related molecules remains poorly understood. In this Review, we discuss the current knowledge of NAD+ metabolism, including limitations of, assumptions about and unappreciated factors that might influence the success or contribute to risks of NAD+ supplementation. We highlight several ongoing controversies in the field, and discuss the role of the microbiome in modulating the availability of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), the presence of multiple cellular compartments that have distinct pools of NAD+ and NADH, and non-canonical NAD+ and NADH degradation pathways. We conclude that a substantial investment in understanding the fundamental biology of NAD+, its detection and its metabolites in specific cells and cellular compartments is needed to support current translational efforts to safely boost NAD+ levels in humans.

DOI: https://doi.org/10.1038/s41580-024-00752-w
Cell Death Dis. 2024 Jul 18. 15(7): 513

Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.

Charles L Bidgood, Lisa K Philp, Anja Rockstroh, Melanie Lehman, Colleen C Nelson, Martin C Sadowski, Jennifer H Gunter.

Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.

DOI: https://doi.org/10.1038/s41419-024-06893-2
Front Cell Dev Biol. 2024 ;12 1308135

Expression of the plasma membrane citrate carrier (pmCiC) in human cancerous tissues-correlation with tumour aggressiveness.

Barbara Schwertner, George Dahdal, Wolfgang Jagla, Luis Grossmann, Konstantin Drexler, Michael P Krahn, Katja Evert, Mark Berneburg, Sebastian Haferkamp, Christine Ziegler, Eric K Parkinson, Grit Zahn, Maria E Mycielska, Andreas Gaumann.

  We have recently shown that cancer cells of various origins take up extracellular citrate through the plasma membrane citrate carrier (pmCiC), a specific plasma membrane citrate transporter. Extracellular citrate is required to support cancer cell metabolism, in particular fatty acid synthesis, mitochondrial activity, protein synthesis and histone acetylation. In addition, cancer cells tend to acquire a metastatic phenotype in the presence of extracellular citrate. Our recent study also showed that cancer-associated stromal cells synthesise and release citrate and that this process is controlled by cancer cells. In the present study, we evaluated the expression of pmCiC, fibroblast activation protein-α (FAP) and the angiogenesis marker cluster of differentiation 31 (CD31) in human cancer tissues of different origins. In the cohort studied, we found no correlation between disease stage and the expression of FAP or CD31. However, we have identified a clear correlation between pmCiC expression in cancer cells and cancer-associated stroma with tumour stage. It can be concluded that pmCiC is increased in cancer cells and in cancer-supporting cells in the tumour microenvironment at the later stages of cancer development, particularly at the metastatic sites. Therefore, pmCiC expression has the potential to serve as a prognostic marker, although further studies are needed.

Keywords:  biomarker; cancer; citrate; plasma membrane citrate carrier (pmCiC); tumour microenvironment

DOI:  https://doi.org/10.3389/fcell.2024.1308135