Cancer & Metabolism最新文献

{"title":"Coordinated histone methylation loss and MYC activation promote translational capacity under amino acid restriction.","authors":"Chen Cheng, Trent Su, Marco Morselli, Siavash K Kurdistani","doi":"10.1186/s40170-025-00399-x","DOIUrl":"10.1186/s40170-025-00399-x","url":null,"abstract":"<p><strong>Background: </strong>Cells adapt to nutrient fluctuations through both signaling and epigenetic mechanisms. While amino acid (AA) deprivation is known to suppress protein synthesis via mTORC1 inactivation, the epigenetic pathways that support cellular adaptation and recovery remain poorly understood. We investigated how chromatin and transcriptional changes contribute to maintaining translational capacity during AA restriction and priming cells for growth upon AA repletion.</p><p><strong>Methods: </strong>Human cells were cultured under amino acid-replete or -depleted conditions, and global histone methylation levels were assessed by Western blotting and ChIP-seq. RNA-seq and chromatin-associated RNA-seq (chromRNA-seq) were used to evaluate gene expression and transcriptional output. Ribosome profiling and [³⁵S]-methionine/cysteine or O-propargyl-puromycin (OPP) incorporation assays measured protein synthesis. Functional contributions of SETD8 and MYC were tested through knockdown and overexpression experiments.</p><p><strong>Results: </strong>AA deprivation induced a selective, genome-wide loss of H4K20me1, particularly from gene bodies, and led to increased MYC expression and binding at promoter regions. These changes were most pronounced at genes encoding ribosomal proteins and translation initiation factors. Although overall protein synthesis declined during AA restriction, these cells showed increased translational capacity evidenced by accumulation of monomeric ribosomes and enhanced translation upon AA repletion. Loss of H4K20me1 was independent of mTORC1 signaling and partly driven by SETD8 protein downregulation. While MYC overexpression alone was insufficient to upregulate translation-related genes, its combination with SETD8 knockdown in nutrient-rich conditions was both necessary and sufficient to induce expression of these genes and enhance protein synthesis.</p><p><strong>Conclusions: </strong>Our findings reveal a chromatin-based mechanism by which cells integrate metabolic status with transcriptional regulation to adapt to amino acid limitation. Loss of H4K20me1 and increased MYC activity act in parallel to prime the translational machinery during AA deprivation, enabling rapid recovery of protein synthesis upon nutrient restoration. This mechanism may help explain how cells maintain competitive growth potential under fluctuating nutrient conditions and has implications for understanding MYC-driven cancer progression.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"29"},"PeriodicalIF":6.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis.","authors":"Ann-Kathrin Daum, Lisa Schlicker, Marc A Schneider, Thomas Muley, Ursula Klingmüller, Almut Schulze, Michael Thomas, Petros Christopoulos, Holger Sültmann","doi":"10.1186/s40170-025-00400-7","DOIUrl":"10.1186/s40170-025-00400-7","url":null,"abstract":"<p><strong>Background: </strong>Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells.</p><p><strong>Methods: </strong>Three-dimensional (3D) spheroid co-cultures comprising ALK-rearranged lung adenocarcinoma cells and CAFs were utilized to model the tumor microenvironment. Single-cell RNA sequencing was performed to uncover transcriptional differences between TKI-treated homotypic and heterotypic spheroids. Functional assays assessed the effects of CAF-conditioned medium and CAF-secreted factors on tumor cell survival, proliferation, lipid metabolism, and downstream AKT signaling. The therapeutic potential of targeting metabolic vulnerabilities was evaluated using pharmacological inhibition of lipid metabolism and by ferroptosis induction.</p><p><strong>Results: </strong>CAFs significantly diminished the apoptotic response of lung tumor cells to ALK inhibitors while simultaneously enhancing their proliferative capacity. Single-cell RNA sequencing identified lipogenesis-associated genes as a key transcriptional difference between TKI-treated homotypic and heterotypic lung tumor spheroids. CAF-conditioned medium and the CAF-secreted factors HGF and NRG1 activated AKT signaling in 3D-cultured ALK-rearranged lung tumor cells, leading to increased de novo lipogenesis and suppression of lipid peroxidation. These metabolic adaptations were critical for promoting tumor cell survival and fostering therapy resistance. Notably, both dual inhibition of ALK and the lipid-regulatory factor SREBP-1, as well as co-treatment with ferroptosis inducers such as erastin or RSL3, effectively disrupted the CAF-driven metabolic-supportive niche and restored sensitivity of resistant lung tumor spheroids to ALK inhibition.</p><p><strong>Conclusions: </strong>This study highlights a critical role for CAFs in mediating resistance to ALK-TKIs by reprogramming lipid metabolism in ALK-rearranged lung cancer cells. It suggests that targeting these metabolic vulnerabilities, particularly through inhibition of lipid metabolism or induction of ferroptosis, could provide a novel therapeutic approach to overcome resistance and improve patient outcomes.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"28"},"PeriodicalIF":6.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can serum metabolic signatures inform on the relationship between healthy lifestyle and colon cancer risk?","authors":"Komodo Matta, Vivian Viallon, Anastasia Chrysovalantou Chatziioannou, Nivonirina Robinot, Roland Wedekind, Christina C Dahm, Agnetha Linn Rostgaard-Hansen, Anne Tjønneland, Therese Truong, Chloé Marques, Pauline Frenoy, Rudolf Kaaks, Renée Turzanski Fortner, Matthias B Schulze, Sabrina Sieri, Mario Fordellone, Rosario Tumino, Fulvio Ricceri, Tonje Braaten, Therese Haugdahl Nøst, Maria-Jose Sánchez, Olatz Mokoroa-Carollo, Sandra Colorado-Yohar, Camino Trobajo-Sanmartín, Keren Papier, Rhea Harewood, Kostas Tsilidis, Salvatore Vaccarella, Mattias Johansson, Elisabete Weiderpass, Cyrille Delpierre, Sebastien Lamy, Kristin Benjaminsen Borch, Pekka Keski-Rahkonen, Elio Riboli, Heinz Freisling, Marc Gunter, Pietro Ferrari","doi":"10.1186/s40170-025-00388-0","DOIUrl":"10.1186/s40170-025-00388-0","url":null,"abstract":"<p><strong>Background: </strong>Colon cancer is strongly influenced by lifestyle factors. Sociodemographic factors like sex and socioeconomic position (SEP) might modulate the relationship between lifestyle and colon cancer risk. Metabolomics offers potential to uncover biological mechanisms linking lifestyle and colon cancer.</p><p><strong>Methods: </strong>Lifestyle and untargeted metabolomic data were available from a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 1,067 colon cancer cases and 1,067 controls matched on age, sex, study centre, and blood collection time. Serum samples were analyzed using liquid chromatography-mass spectrometry. The Healthy Lifestyle Index (HLI) score was derived from smoking habits, alcohol intake, body mass index (BMI), physical activity, and diet. Penalised regression was applied in controls to derive metabolic signatures for the HLI and the lifestyle components. Associations of lifestyle factors and the metabolic signatures with colon cancer risk were estimated in conditional logistic regression models, overall and by sex and SEP.</p><p><strong>Results: </strong>The HLI score was inversely associated with colon cancer risk, with an odds ratio (OR) per 1-standard deviation (SD) increment equal to 0.79; 95% CI: 0.71, 0.87. The metabolic signature of HLI, comprising 130 features, was moderately correlated with HLI (r = 0.59; 94% CI: 0.56, 0.61), and was inversely associated with colon cancer risk (OR = 0.86; 95% CI: 0.78, 0.95). After adjustment for the HLI score, the association of the metabolic signature of HLI and colon cancer risk was null (OR = 1.00, 95% CI 0.88, 1.13). Associations of lifestyle factors and the metabolic signature with colon cancer risk were consistently stronger for men than for women and did not differ by SEP.</p><p><strong>Conclusions: </strong>In this study across seven European countries, healthy lifestyle was inversely associated with colon cancer risk, with stronger associations in men than women and no differences across SEP. However, the serum metabolic signatures after adjustment for lifestyle factors were not found to be associated with colon cancer risk, suggesting that lifestyle impacts colon cancer through mechanisms not captured by the signatures.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"30"},"PeriodicalIF":6.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A role of arginase-1-expressing myeloid cells in cachexia.","authors":"Lamsal Apsana, Andersen Sonja Benedikte, Nonstad Unni, Kurganovs Natalie Jayne, Skipworth Richard Je, Bjørkøy Geir, Pettersen Kristine","doi":"10.1186/s40170-025-00396-0","DOIUrl":"10.1186/s40170-025-00396-0","url":null,"abstract":"<p><strong>Background: </strong>Despite decades of efforts to find successful treatment approaches, cachexia remains a major unmet medical need. This condition, that affects patients with diverse underlying conditions, is characterized by severe muscle loss and is associated with reduced quality of life and limited survival. Search for underlying mechanisms that may guide cachexia treatment has mainly evolved around potential atrophy-inducing roles of inflammatory mediators, and in cancer patients, tumor-derived factors. Recently, a new paradigm emerged as it is becoming evident that specific immune cells inhabit atrophic muscle tissue. Arginase 1 (Arg1) expression is characteristic of these immune cells. Studies of potential contributions of these immune cells to loss of muscle mass and function is in its infancy, and the contribution of ARG1 to these processes remains elusive.</p><p><strong>Methods: </strong>Analyses of RNA sequencing data from murine cachexia models and comprehensive, unbiased open approach proteomics analyses of skeletal myotubes was performed. In vitro techniques were employed to evaluate mitochondrial function and capacity in skeletal muscle cells and cardiomyocytes. Functional bioassays were used to measure autophagy activity. ARG1 level in patients' plasma was evaluated using ELISA, and the association between ARG1 level and patient survival, across multiple types of cancer, was examined using the online database Kaplan-Meier plotter.</p><p><strong>Results: </strong>In line with arginine-degrading activity of ARG1, we found signs of arginine restriction in atrophic muscles. In response to arginine restriction, mitochondrial functions and ATP generation was severely compromised in both skeletal muscle cells and in cardiomyocytes. In skeletal muscle cells, arginine restriction enhanced the expression of autophagic proteins, suggesting autophagic degradation of cellular content. Reduction in mitochondria marker TIMM23 supports selective autophagic degradation of mitochondria (mitophagy). In arginine starved cardiomyocytes, mitochondrial dysfunction is accompanied by both increased bulk autophagy and mitophagy. In cancer patients, we found an association between ARG1 expression and accelerated weight loss and reduced survival, further supporting a role of ARG1-producing cells in cachexia pathogenesis.</p><p><strong>Conclusion: </strong>Together, our findings point to a mechanism for cachexia which depends on expansion of ARG1-expressing myeloid cells, local restriction of arginine, loss of mitochondrial capacity and induced catabolism in skeletal muscle cells and in the heart.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"27"},"PeriodicalIF":6.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights.","authors":"Shyng-Shiou F Yuan, Anupama Vadhan, Hieu D H Nguyen, Pang-Yu Chen, Chih-Huang Tseng, Ching-Hu Wu, Yu-Chieh Chen, Yi-Chia Wu, Stephen Chu-Sung Hu, Steven Lo, Ming-Feng Hou, Yen-Yun Wang","doi":"10.1186/s40170-025-00397-z","DOIUrl":"10.1186/s40170-025-00397-z","url":null,"abstract":"<p><p>Breast cancer remains the most prevalent malignancy among women globally, with its complexity linked to genetic variations and metabolic alterations within tumor cells. This study investigates the role of fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, in breast cancer progression. Our findings reveal that FH mRNA and protein levels are significantly upregulated in breast cancer tissues and correlate with poor patient prognosis and aggressive tumor characteristics. Using in vitro and in vivo models, we demonstrate that FH overexpression enhances breast cancer cell proliferation, migration, and invasion through metabolic reprogramming and by increasing reactive oxygen species (ROS) production. Furthermore, we identify matrix metalloproteinase 1 (MMP1) as a downstream effector of FH, linked to p21 downregulation, elucidating a novel regulatory pathway influencing tumor behavior. Interestingly, unlike its tumor-suppressing role in other cancer types, this study highlights FH's oncogenic potential in breast cancer. Our results suggest that FH enhances cancer cell viability and aggressiveness via both catalytic and non-catalytic mechanisms. This work not only underscores the metabolic adaptations of breast cancer cells but also proposes FH as a potential biomarker and therapeutic target for breast cancer management.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"26"},"PeriodicalIF":6.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of physiological media on acute myeloid leukemia bioenergetics and cell proliferation.","authors":"Brett R Chrest, McLane M Montgomery, Raphael T Aruleba, Polina Krassovskaia, Emely A Pacheco, James T Hagen, Kayla J Vandiver, Kang Tung, Molly K Alexander, Nicholas C Williamson, Joshua G Taylor, Riley N Bessetti, Heather A Belcher, Filip Jevtovic, Zoe S Terwilliger, Everett C Minchew, Tonya N Zeczycki, Linda May, Nicholas T Broskey, Christopher B Geyer, Karen Litwa, Espen E Spangenburg, Johanna L Hannan, Jessica M Ellis, Joseph M McClung, P Darrell Neufer, Kelsey H Fisher-Wellman","doi":"10.1186/s40170-025-00395-1","DOIUrl":"10.1186/s40170-025-00395-1","url":null,"abstract":"<p><p>Increasing emphasis has been placed on improving the physiological relevance of cell culture media with formulations such as Human Plasma-Like Medium (HPLM). Given that shifts in mitochondrial metabolism and nutrient use are emerging as anti-cancer targets, the present study sought to investigate the impact of culture media formulation on mitochondrial bioenergetics and cancer cell growth. To do this, we used acute myeloid leukemia (AML) cells and compared acute and chronic effects of HPLM versus different supraphysiological medias. The AML mitochondrial phenotype was largely unaffected by exposure to either physiological or supraphysiological medias, establishing that the key features of AML mitochondria remain phenotypically stable under diverse nutrient conditions and proliferation rates. Both acute and chronic culturing in HPLM slowed AML cell proliferation. However, merely identifying and supplementing single nutrients that were deficient in HPLM did not improve proliferation and was not sufficient to pinpoint actionable fuel preferences. Transferring cells back to native Iscove's Modified Dulbecco's Medium (IMDM) media immediately restored the proliferative phenotype, suggesting responsiveness to the entirety of the nutrient environment. Supraphysiological culture medias other than IMDM were all characterized by slower proliferation; however, none were associated with changes in cell viability, demonstrating that the native culture medium is optimal if the experimental aim is maximal growth. Despite Dulbecco's Modified Eagle Medium (DMEM) being similar in nutrient composition to IMDM and categorized as supraphysiological, both acute and chronic culturing in DMEM resulted in slower growth, akin to what was observed with HPLM. Altogether, independent of growth, AML mitochondria remain largely unperturbed by changes in the culture media, and rather than specific nutrients or physiological relevance, AML cell proliferation is influenced by the complete nutrient profile.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"25"},"PeriodicalIF":6.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12105319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved VPS4B O-GlcNAc modification triggers lipid droplets transferring from adipocytes to nasopharyngeal carcinoma cells.","authors":"Haimeng Yin, Ying Shan, Qin Zhu, Ling Yuan, Feng Ju, Yu Shi, Yumo Han, Rui Wu, Tian Xia, Kaiwen Zhang, Yiwen You, Bo You","doi":"10.1186/s40170-025-00393-3","DOIUrl":"10.1186/s40170-025-00393-3","url":null,"abstract":"<p><strong>Background: </strong>The tumor microenvironment (TME) supplies critical metabolites that support cancer cell survival and progression. Adipocytes support tumor progression by secreting free fatty acids (FFAs) and adipokines; however, the role and mechanisms underlying lipid droplet (LD) release from adipocytes remain elusive.</p><p><strong>Methods: </strong>Using two nasopharyngeal carcinoma (NPC) cell lines and primary human pre-adipocytes (HPA), we evaluate the effect of LDs on cell growth, proliferation, colony formation, and migration. We also assess the roles of LD on the tumor progression in vivo. Using RNA-seq analysis, we elucidate the effect of hypoxic NPC cell-derived exosomes (H-exo) on the gene expression profile of adipocytes. By co-culture system, we investigated the effect of vacuolar protein sorting 4 homolog B (VPS4B)-annexin A5 (ANXA5) interaction on adipocyte LD maturity and release.</p><p><strong>Results: </strong>Herein, we report that LDs, rather than FFAs, are the primary lipid form transferred from adipocytes to NPC cells, enhancing cancer progression. NPC cells internalize LDs directly via macropinocytosis, while H-exo induces oxidative stress and membrane fluidity in adipocytes, leading to LD release. Transcriptomic and proteomic analyses reveal that VPS4B triggers LD release by interacting with ANXA5, and low LKB1 in H-exo enhances VPS4B O-linked N-acetylglucosamine (O-GlcNAc) modification through the inhibition of serine/threonine kinase 11 (STK11/LKB1)-AMP-activated protein kinase (AMPK) pathway and activation of the hexosamine biosynthesis pathway (HBP) flux.</p><p><strong>Conclusions: </strong>This study uncovers critical mechanisms of LD transfer in the TME, suggesting new therapeutic avenues in NPC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"24"},"PeriodicalIF":6.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12100974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate dehydrogenase A-coupled NAD⁺ regeneration is critical for acute myeloid leukemia cell survival.","authors":"Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel","doi":"10.1186/s40170-025-00392-4","DOIUrl":"10.1186/s40170-025-00392-4","url":null,"abstract":"<p><strong>Background: </strong>Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD⁺.</p><p><strong>Methods: </strong>We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry.</p><p><strong>Results: </strong>Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD⁺ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD⁺/NADH ratio in AML cells. Continuous intracellular NAD⁺ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition.</p><p><strong>Conclusions: </strong>Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD⁺/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD⁺ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"22"},"PeriodicalIF":6.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S-adenosylmethionine metabolism shapes CD8⁺ T cell functions in colorectal cancer.","authors":"Xiaohua Yang, Tianzhang Kou, Hongmiao Wang, Ji Zhu, Zheng-Jiang Zhu, Yuping Cai","doi":"10.1186/s40170-025-00394-2","DOIUrl":"10.1186/s40170-025-00394-2","url":null,"abstract":"<p><p>Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8⁺ T cells. Instead, cancer cells outcompete CD8⁺ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8⁺ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"23"},"PeriodicalIF":6.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and impact of microbiota-derived metabolites in ascites of ovarian and gastrointestinal cancer.","authors":"Sisi Deng, Wooyong Kim, Kefan Cheng, Qianlu Yang, Yogesh Singh, Gyuntae Bae, Nicolas Bézière, Lukas Mager, Stefan Kommoss, Jannik Sprengel, Christoph Trautwein","doi":"10.1186/s40170-025-00391-5","DOIUrl":"10.1186/s40170-025-00391-5","url":null,"abstract":"<p><strong>Background: </strong>Malignant ascites is a common complication of advanced ovarian cancer (OC) and gastrointestinal cancer (GI), significantly impacting metastasis, quality of life, and survival. Increased intestinal permeability can lead to blood or lymphatic infiltration and microbial translocation from the gastrointestinal or uterine tract. This study aimed to identify microbiota-derived metabolites in ascites from OC (stages II-III and IV) and GI patients, assessing their roles in tumor progression.</p><p><strong>Methods: </strong>Malignant ascites samples from 18 OC and GI patients were analyzed using a four-dimensional (4D) untargeted metabolomics approach combining reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC) with trapped ion mobility spectrometry time-of-flight mass spectrometry (timsTOF-MS). Additonally, a targeted flow cytometry-based cytokine panel was used to screen for inflammatory markers. Non-endogenous, microbiota-derived metabolites were identified through the Human Microbial Metabolome Database (MiMeDB).</p><p><strong>Results: </strong>OC stage IV exhibited metabolic profiles similar to GI cancers, while OC stage II-III differed significantly. Stage IV OC patients exhibited higher levels of 11 typically microbiome-derived metabolites, including 1-methylhistidine, 3-hydroxyanthranilic acid, 4-pyridoxic acid, biliverdin, butyryl-L-carnitine, hydroxypropionic acid, indole, lysophosphatidylinositol 18:1 (LPI 18:1), mevalonic acid, N-acetyl-L-phenylalanine, and nudifloramide, and lower levels of 5 metabolites, including benzyl alcohol, naringenin, o-cresol, octadecanedioic acid, and phenol, compared to stage II-III. Correlation analysis revealed positive associations between IL-10 and metabolites such as glucosamine and LPCs, while MCP-1 positively correlated with benzyl alcohol and phenol.</p><p><strong>Conclusion: </strong>4D metabolomics revealed distinct metabolic signatures in OC and GI ascites, highlighting microbiota-derived metabolites involved in lipid metabolism and inflammation. Metabolites like 3-hydroxyanthranilic acid, indole, and naringenin may serve as markers of disease progression and underscore the microbiota's role in shaping malignant ascites and tumor biology.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"21"},"PeriodicalIF":6.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}