Cancer & Metabolism最新文献

{"title":"Fos-induced osteosarcoma growth causes a cachexia-like phenotype in mice and correlates with high Fgf21 serum levels.","authors":"Julia Luther, Armelle Carreau, Christina Baldauf, Mona Neven, Till Koehne, Michael Amling, Thorsten Schinke","doi":"10.1186/s40170-025-00417-y","DOIUrl":"10.1186/s40170-025-00417-y","url":null,"abstract":"<p><p>BACKGROUND: The dimeric AP-1 transcription factor has been described as a regulator of bone metabolism, but also of adipocyte biology. More specifically, its family members adopt specific functions in the regulation of adipocyte differentiation and adipose tissue hypoxia, but also in controlling lipolysis, energy expenditure and insulin sensitivity. METHODS: In this study, we analyzed the role of the AP-1 family member Fos, whose ubiquitous over-expression in transgenic mice has been described to cause osteosarcoma formation, on adipose tissue, glucose and lipid metabolism. More specifically, we analyzed the metabolic phenotype of the respective mouse model by histological analyses, monitoring gene expression, determination of serum parameters and ex vivo adipogenesis assays. RESULTS: We show that FosTg mice additionally display an age-dependent loss of white adipose tissue, which is associated with reduced adipocyte size. Quantitative real-time PCR analyses of white adipose tissue as well as in vitro studies using adipocyte-derived stromal cells excluded a cell-autonomous defect in adipocyte differentiation. However, FosTg mice displayed low circulating glucose levels along with increased glucose tolerance and insulin sensitivity. By proteomic analysis we identified elevated serum levels of fibroblast growth factor 21 (Fgf21) in FosTg mice which could explain the observed reduced hepatic lipogenesis and white adipose tissue mass. Most importantly, we demonstrated that this metabolic phenotype is dependent on osteosarcoma formation by crossing the FosTg mice with mice deficient for Rsk2, a kinase necessary for tumor growth. Moreover, we could show a direct correlation between tumor burden and Fgf21 serum levels in our mouse model. CONCLUSION: In summary, our data identify Fgf21 as a potential regulator of glucose and lipid metabolism in Fos transgenic osteosarcoma-bearing mice, thereby supporting its essential function in the regulation of the metabolic phenotype associated with cancer cachexia. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13218021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112506","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":"The FGL1-LAG-3 axis attenuates melanoma-induced cachexia in mice.","authors":"Weitao Liu, Lining Wang, Shumei Jin, Tongbin Liu, Yingchen Qian, Peng Lin","doi":"10.1186/s40170-025-00418-x","DOIUrl":"10.1186/s40170-025-00418-x","url":null,"abstract":"<p><p>Cachexia is a debilitating condition characterized by the wasting of adipose and skeletal muscle tissues, resulting in significant weight loss and frailty. It is responsible for 20% of cancer-related mortalities. Despite its clinical significance, the precise mechanisms underlying cachexia remain inadequately understood. Our gene expression analysis of white adipose tissues has identified an upregulation of fibrinogen-like protein 1 (FGL1) in B16F10 tumor-bearing mice. In this study, we demonstrate that the intraperitoneal administration of FGL1 protein mitigates tumor-induced wasting of adipose and muscle tissues in mice. Correspondingly, FGL1 treatment reverses the expression patterns of genes associated with lipid metabolism and muscle degradation. Mechanistically, our research establishes that lymphocyte activation gene-3 (LAG-3) serves as a critical mediator of FGL1’s anti-cachexia effects. These findings suggest that FGL1 acts as a crucial intermediary between tumor presence and the processes of adipose catabolism and muscle wasting, thereby identifying the FGL1-LAG-3 signaling axis as a promising therapeutic target for cancer cachexia.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":"2"},"PeriodicalIF":5.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12869940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917079","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":"The role of deoxycholic acid in macrophage polarization and remodeling of the tumor microenvironment during colorectal adenoma-carcinoma transition.","authors":"Yujing Liu, Jie Yin, Lu Lu, Jiashu Pan, Gaoxuan Shao, Yangxian Xu, Guang Ji, Hanchen Xu","doi":"10.1186/s40170-025-00416-z","DOIUrl":"10.1186/s40170-025-00416-z","url":null,"abstract":"<p><p>During the progression from colorectal adenoma to colorectal cancer (CRC), the inflammatory state of the tumor microenvironment (TME) evolves in parallel with the epithelial‒mesenchymal transition (EMT) process. Among the key players, macrophages serve as pivotal mediators of inflammation-cancer transformation and are closely associated with these dynamic changes. Deoxycholic acid (DCA), a critical bile acid metabolite involved in CRC development, has been implicated in tumorigenesis; however, its role in macrophage polarization and the adenoma-carcinoma sequence remains unclear. In this study, we analyzed clinical cell types and DCA levels in colorectal adenomas and carcinomas to elucidate the correlation between DCA and macrophages in CRC. Furthermore, we investigated the mechanistic role of DCA in promoting M2-like polarization of tumor-associated macrophages and validated the impact of DCA on the EMT-associated Wnt/β-catenin pathway and inflammation-associated NF-κB signaling pathway in CRC model mice. Our findings may provide novel strategies for prognostic biomarkers and precise bile acid metabolism-based interventions in CRC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"47"},"PeriodicalIF":5.9,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12709865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767264","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":"Sustained reductions in valine and isoleucine mediate anti-cancer pharmacological effects of inhibiting amino acid transporter LAT1 in cancer cells.","authors":"Kou Nishikubo, Ryuichi Ohgaki, Hiroki Okanishi, Minhui Xu, Yoshikatsu Kanai","doi":"10.1186/s40170-025-00415-0","DOIUrl":"10.1186/s40170-025-00415-0","url":null,"abstract":"<p><strong>Background: </strong>L-type amino acid transporter 1 (LAT1; SLC7A5), which preferentially transports large neutral amino acids (LNAAs), is highly upregulated in various cancers and represents a promising therapeutic target. The first-in-class LAT1-specific inhibitor, nanvuranlat (JPH203, KYT-0353), has exhibited potent anti-cancer effects and is under clinical evaluation. However, alterations in the amino acid availability in cancer cells underlying its pharmacological activities remain to be elucidated.</p><p><strong>Methods: </strong>Amino acids in nanvuranlat-treated cancer cells were measured by high-performance liquid chromatography. LAT1 knockdown was performed using siRNA. To mimic LAT1 inhibition, cancer cells were incubated in culture media lacking specific LNAA(s) reduced by nanvuranlat. The consequences of these treatments were compared by cell-based assays, including analyses of amino acid contents, cell growth, amino acid-related signaling pathways, cell cycle, ATP production rate, and transcriptomes by RNA sequencing. Metabolome of nanvuranlat-treated and untreated cells was compared by mass spectrometry. The effects of nanvuranlat on amino acid composition were also examined in three-dimensional cancer cell spheroids.</p><p><strong>Results: </strong>Both pharmacological and genetic inhibition of LAT1 preferentially and continuously reduced valine, isoleucine, and tryptophan in pancreatic cancer MIA PaCa-2 cells. Nanvuranlat induced similar alterations in intracellular amino acids in multiple cancer cell lines. Depletion of these amino acids from culture media selectively lowered their intracellular concentrations, recapitulating the effects of nanvuranlat on cell growth, amino acid-related mTORC1/GAAC signaling pathways, and cell cycle. Deprivation of valine or isoleucine exhibited more pronounced impacts than tryptophan in all assays. As a novel pharmacological action of nanvuranlat mediated by the reductions in valine and isoleucine, we revealed downregulation of multiple genes in the TCA cycle and respiratory chain, accompanied by a decreased mitochondrial ATP production rate. Consistently, metabolomics revealed broad decreases in the TCA cycle intermediates by LAT1 inhibition. Nanvuranlat also similarly influenced the amino acid levels in cancer cell spheroids.</p><p><strong>Conclusions: </strong>Reductions in valine and isoleucine in cancer cells primarily account for the multifaceted anti-cancer pharmacological activities of LAT1 inhibition by nanvuranlat. This study establishes the molecular basis for LAT1-targeted therapy and highlights growth-promoting processes in cancer cells that can be exploited pharmacologically by modulating the availability of specific amino acids.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"46"},"PeriodicalIF":5.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12673697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660468","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":"Cdk5 regulates glutamine metabolism in colorectal cancer via the EZH2-GLS1 axis.","authors":"Qilong Wu, Xiaotong Zhu, Xinxin Wan, Xinjie Lu, Jiayan Chen, Zhe Ying, Yan Li, Xing Hu, Jiahai Lu, Yongliang Lou, Xiang Li","doi":"10.1186/s40170-025-00414-1","DOIUrl":"10.1186/s40170-025-00414-1","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a globally prevalent malignancy that poses a substantial threat to human health. Despite advancements in prevention, diagnosis, and treatment, CRC remains a formidable clinical challenge due to the incomplete elucidation of its pathological mechanisms. Glutamine, an abundant amino acid, exerts pivotal roles in energy production, redox homeostasis, macromolecular biosynthesis, and signal transduction within cancer cells. Elucidating the role of glutamine in CRC pathogenesis is therefore of profound significance. In this study, we investigated the regulatory role of Cyclin-dependent kinase 5 (Cdk5) in glutamine metabolism in CRC, employing both human CRC cell models and murine models. Our findings demonstrated that Cdk5 knockdown accelerated glutamine uptake while suppressing the proliferation of CRC cells. Further exploration of the underlying molecular mechanisms revealed that Cdk5 physically interacts with EZH2. Besides, Cdk5 phosphorylates EZH2 at specific sites, and then the PRC2 complex (centered around EZH2) catalyzes the production of H3K27me3, an inhibitory marker, to regulate the expression of genes involved in glutamine metabolism. At the same time, we also found that modulation of the Cdk5-EZH2 axis alters the epigenetic landscape of genes associated with glutamine transporters and tricarboxylic acid cycle (TCA) enzymes, resulting in reduced mitochondrial activity, impaired glutamine utilization in the TCA cycle, and decreased ATP production-collectively impacting the global glutamine metabolic processes in CRC cells. In in vivo experiments utilizing a murine CRC model, we established five experimental groups. Results showed that Dinaciclib treatment suppressed tumor growth in the CRC model, with this inhibitory effect being further potentiated upon combination with glutamine deprivation. These findings not only uncover the intricate interplay between Cdk5, EZH2, and glutamine metabolism in CRC but also offer novel insights into the pathogenic mechanisms of CRC and identify potential therapeutic targets.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":"1"},"PeriodicalIF":5.3,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12790122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581734","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":"Matrix composition and glucose availability cooperatively determine cancer spheroid bioenergetics in 3D hydrogels.","authors":"Paula Guerrero-López, Gorana Drobac, Eduardo A Silva, Hanne R Hagland, José Manuel García-Aznar","doi":"10.1186/s40170-025-00413-2","DOIUrl":"10.1186/s40170-025-00413-2","url":null,"abstract":"<p><p>The interplay between extracellular matrix (ECM) biophysical properties and nutrient availability is crucial in cancer metabolism, but the specific influence of different ECM components remains unclear. This study investigates how collagen and fibrin 3D hydrogels, with varying stiffness, alongside different glucose concentrations, differentially regulate the metabolic phenotype of A549 lung and Panc1 pancreatic cancer spheroids. We observed that while glucose availability predominantly dictates metabolic profiles in collagen-based matrices, particularly influencing A549 cell behavior, metabolic adaptation in fibrin hydrogels was co-regulated by matrix properties and glucose levels. Notably, lung cancer cells shifted towards glycolysis under high glucose in collagen, whereas pancreatic cancer cells, inherently more glycolytic, exhibited metabolic rigidity, especially under low glucose, irrespective of collagen stiffness. Conversely, fibrin matrices generally induced a less noticeable, more quiescent metabolic state in both cancer cells, particularly under glucose deprivation. Specifically, higher collagen concentrations tended to support anaerobic metabolism, especially under glucose scarcity. The findings of this study reveal a hierarchical interplay where ECM composition tunes the sensitivity of cancer cells to nutrient availability, underscoring the necessity of integrating both matrix-specific mechanical cues and nutrient gradients in advanced 3D tumor models for identifying context-dependent metabolic vulnerabilities. This could have potential implications for designing future effective therapeutic strategies targeting the tumor microenvironment.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"45"},"PeriodicalIF":5.9,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12628585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145548505","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":"Correction: A role of arginase-1-expressing myeloid cells in cachexia.","authors":"Apsana Lamsal, Sonja Benedikte Andersen, Unni Nonstad, Natalie Jayne Kurganovs, Richard Je Skipworth, Geir Bjørkøy, Kristine Pettersen","doi":"10.1186/s40170-025-00412-3","DOIUrl":"10.1186/s40170-025-00412-3","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"44"},"PeriodicalIF":5.3,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12593791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470742","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":"Metabolic reprogramming in diffuse intrinsic pontine gliomas (DIPG): dual inhibition of mitochondrial oxidative phosphorylation and lactate metabolism to enhance anti-tumor and radiosensitizing effects in DIPG cells.","authors":"Han Shen, Quy-Susan Huynh, Faiqa Mudassar, Cecilia Chang, Brian Gloss, Prunella Ing, Shiyong Ma, Harriet Gee, Eric Hau, Kristina M Cook","doi":"10.1186/s40170-025-00411-4","DOIUrl":"10.1186/s40170-025-00411-4","url":null,"abstract":"<p><p>BACKGROUND: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), are universally fatal pediatric brain tumors with no effective treatments. DIPG tumors actively utilize mitochondrial oxidative phosphorylation (OXPHOS). Inhibition of Complex I (a core OXPHOS component) by phenformin radiosensitizes DIPG in vitro and in vivo. However, phenformin’s clinical application is limited by its risk of lactic acidosis. We investigated whether co-administration of the pyruvate-dehydrogenase-kinase (PDK) inhibitor dichloroacetate (DCA) can mitigate phenformin-induced acidosis while enhancing its anti-tumor activity. METHODS: Patient-derived DIPG cells (SU-DIPG17, HSJD-DIPG007, SU-DIPG-VI) were treated with phenformin (0.625 mM), DCA (25 mM) or both. Mitochondrial and glycolytic flux (oxygen consumption rate (OCR) / extracellular acidification rate (ECAR)), ATP production, Reactive Oxygen Species (ROS), cell-cycle and apoptosis were quantified alongside RNA-seq and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS)/MS metabolomics. Hypoxia was measured in neurospheres using fluorescence. Radiosensitization was assessed by γ-H2AX foci and clonogenic survival. In vivo, HSJD-DIPG007 orthotopic xenografts received phenformin (125 mg/kg/day) and DCA (250 mg/kg/day) by oral gavage for 4 weeks, alone or with focal brain-stem irradiation (2 Gy × 10); tumor immunohistochemistry and survival were recorded. RESULTS: DCA alone shifted glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS), reducing ECAR and intracellular lactate. When combined with phenformin, DCA significantly suppressed phenformin-induced glycolysis and ECAR while further reducing ATP. In vitro, this combination induced synergistic cell-cycle arrest, apoptosis, and ROS-induced DNA damage. Multi-omics integration revealed coordinated repression of glycolytic/ hypoxia-inducible factor (HIF) programs and diversion of glucose into redox-supportive pentose-phosphate pathways. Hypoxic staining confirmed reduced hypoxia and HIF-1α in 3D neurospheroids. The combination produced additional in vitro radiosensitization, with the phenformin + DCA + radiation triple regimen achieving the greatest γ-H2AX persistence and clonogenic kill. In mice, the triple combination schedule incurred systemic toxicity, reflected from weight loss, and did not extend survival over 4 weeks treatment. CONCLUSIONS: DCA effectively counteracts phenformin-induced lactic acidosis in vitro yet heightens metabolic stress and radiosensitization in DIPG cells, providing proof-of-concept that a carefully chosen metabolic partner can boost tumor control. However, weight loss in vivo limited the length of treatment schedule and optimizing dose and schedule, or selecting safer mitochondrial inhibitors with PDK blockade, will be essential next steps before determining in vivo efficacy of this metabolic strategy. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"43"},"PeriodicalIF":5.9,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12570633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400072","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":"Interplay between malic enzyme 2, de novo serine synthesis, and the malate-aspartate shuttle drives metabolic adaptation in triple-negative breast cancer.","authors":"Jin Heon Jeon, Mark D Slayton, Ben Krinkel, Olamide Animasahun, Ajay Shankaran, Fulei Wuchu, Minal Nenwani, Zackariah Farah, Julia Burke, Abhinav Achreja, Brisilda Nilaj, Kerslee Kohagen, Yi-Hsien Eu, Alyssa Rosenfeld, Mason Collard, Liwei Bao, Xu Cheng, Celina Kleer, Christopher Squire, Kerry Loomes, Deepak Nagrath, Sofia D Merajver","doi":"10.1186/s40170-025-00410-5","DOIUrl":"10.1186/s40170-025-00410-5","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer with poor clinical outcomes. Malic enzyme 2 (ME2) is a mitochondrial enzyme that catalyzes the conversion of malate to pyruvate and has been proposed as a therapeutic target. ME2 is highly expressed in many cell types including TNBC cells. We sought to define the molecular and cellular consequences of ME2 inhibition to facilitate its clinical translation. Here, we systematically evaluated the cellular and molecular effects of ME2 knockdown (ME2kd) in multiple TNBC models. ME2kd had heterogeneous effects on proliferation, migration, and metabolic flexibility in TNBC cell lines. ME2kd MDA-MB-468 xenografts in nude mice grew significantly slower and conferred prolonged host survival. ME2kd caused distinct shifts in mitochondrial respiration and glycolysis, whereas metabolomic and transcriptomic analyses revealed altered tricarboxylic acid (TCA) cycle flux, glutamine consumption, and serine/glycine metabolism, partly through changes in malate-aspartate shuttle (MAS) activity. The interplay between ME2, the serine synthesis pathway and the MAS was investigated with metabolite deprivation and co-knockdown assays. Importantly, we determined the crystal structure of ME2 bound to the small-molecule inhibitor NPD-389 and identified the binding interactions that drive the inhibitory response. These findings help to clarify the role of ME2 in TNBC phenotypes and highlight the therapeutic potential of ME2 inhibition in precision oncology.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"42"},"PeriodicalIF":5.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291284","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":"The integration of single-cell and metabolomics reveals the increase of oxidative phosphorylation during the liver metastasis of colorectal cancer.","authors":"Tianyu Liu, Sizheng Sun, Yicheng Huang, Yiming E, Wenyuan Li, Fanggui Xu, Zhengxia Liu, Xiagang Luo, Chen Lu, Chunzhao Yu","doi":"10.1186/s40170-025-00408-z","DOIUrl":"10.1186/s40170-025-00408-z","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is among the most prevalent malignant tumors, with liver metastasis as the leading cause of mortality. Although metabolic reprogramming is known to play a crucial role in tumor metastasis, our understanding of this process during colorectal cancer liver metastasis (CRLM) remains limited.</p><p><strong>Methods: </strong>A stepwise mouse model of CRC liver metastasis was developed, and metabolomic profiling was performed to verify model stability and identify metabolic changes. Single-cell RNA sequencing (scRNA-seq) was used to assess oxidative phosphorylation (OXPHOS) activity within the metastatic tumor microenvironment (TME). Additionally, spatial transcriptomics (ST) was conducted to elucidate the spatial distribution of metabolic phenotypes within metastatic sites. Finally, in vivo experiments were conducted by administering TGFβ inhibitor (LY2157299) or OXPHOS inhibitor (IACS-010759) to evaluate the potential for liver metastasis, and in vitro, the functions of HCT116 and SW620 cells were assessed through Transwell assays and oxygen consumption rate (OCR) measurements.</p><p><strong>Results: </strong>Metabolomic profiling revealed heightened tricarboxylic acid (TCA) cycle activity in liver metastases. ScRNA-seq analysis showed increased OXPHOS in metastatic cells, including a highly malignant cell subtype characterized by augmented OXPHOS. Further analysis identified a significant upregulation of OXPHOS associated with TGFβ pathway activation. ST localized this OXPHOS -enriched subtype within metastatic tissue. Both in vivo and in vitro experiments demonstrate that inhibition of TGFβ signaling reduces OXPHOS activity, thereby attenuating the progression of colorectal cancer liver metastasis.</p><p><strong>Conclusions: </strong>This study identifies OXPHOS upregulation as a key metabolic alteration during CRC liver metastasis, which could be induced by TGFβ signaling pathway. These findings contribute to a refined understanding of CRC metabolic adaptation in liver metastases and may inform therapeutic strategies targeting OXPHOS in advanced CRC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"41"},"PeriodicalIF":5.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257556","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}