bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–06–29
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Free Methylglyoxal and Lactate Produced and Released by Cultured Cancer and Non-Cancer Cells: Implications for Tumor Growth and Development.
  2. Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy.
  3. Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.
  4. Ectopic expression of GDF15 in cancer-associated fibroblasts enhances melanoma immunosuppression via the GFRAL/RET cascade.
  5. Vascular collapse leads to muscle wasting in cancer cachexia.
  6. Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting-Induced Proteolysis.
  7. ULK1-dependent phosphorylation of OGT instructs the tumorigenicity of O-GlcNAcylation.
  8. ATF4 in proximal tubules modulates kidney function and modifies the metabolome.
  9. Beyond boundaries: exploring the role of extracellular vesicles in organ-specific metastasis in solid tumors.
  10. RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation.
  1. Cells. 2025 Jun 19. pii: 931. [Epub ahead of print]14(12):
    Free Methylglyoxal and Lactate Produced and Released by Cultured Cancer and Non-Cancer Cells: Implications for Tumor Growth and Development.
    Dominique Belpomme, Philippe Irigaray, Jean-Marc Alberto, Clément Poletti, Charlotte Hinault-Boyer, Stéphanie Lacomme.
      We have previously shown that in cancer patients, free methylglyoxal (MG), a side-product of glycolysis, is recovered from tumors at significantly higher levels than from their corresponding non-cancerous tissues. We also recently confirmed our initial experimental finding that in these patients, free MG peripheral blood levels correlate positively with tumor growth, making free MG levels a new metabolic biomarker of tumor growth of interest to detect cancer and clinically follow cancer patients with no available biomarkers. Now we measure free MG and lactate produced by different cancer and normal cells cultured at low or high glucose concentration and in normoxic or hypoxic conditions to question whether cancer cells and non-cancer cells in tumors produce and release free MG and lactate. Surprisingly, we found that normal fibroblastic and endothelial cell lines grown in normoxic conditions produce and release high free MG levels, which we confirmed for non-transformed normal fibroblasts, albeit at significantly lower levels. Cancer cells generally significantly increased their free MG production and release when cultured in high glucose concentration, while normal cells generally did not. Furthermore, in normoxic conditions, normal fibroblastic cells, in addition to free MG, may produce and release lactate. From this data, we propose that in malignant tumors, both cancer and fibroblastic stromal cells may contribute to tumor growth and development by producing via glycolysis both free MG and D-lactate, which, in addition to L-lactate, may be part of the core hallmark of cell metabolic reprogramming in cancer.
    Keywords:  Warburg effect; cancer cells; cancer-associated fibroblasts; cell metabolic reprogramming; glycolysis; lactate; methylglyoxal; stromal cells; tumor growth; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells14120931
  2. Nat Rev Immunol. 2025 Jun 27.
    Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy.
    Evripidis Lanitis, Melita Irving, George Coukos.
      The formation of new blood vessels - known as angiogenesis - is essential for the growth and spread of solid tumours. It is promoted by the hypoxic conditions that develop in growing tumours and drive the expression of pro-angiogenic growth factors by tumour cells and various stromal cells. However, the tumour-associated vasculature (TAV) generated by angiogenesis is abnormal and is a key barrier to T cell entry into tumours. Moreover, the TAV creates a hostile microenvironment owing to an accumulation of suppressive immune cells, hypoxic and acidic conditions, and high interstitial pressure, which all limit the function and survival of effector T cells. Here, we present the mechanisms of T cell migration into tumours, including via high endothelial venules, and the importance of tertiary lymphoid structures, which function as privileged sites for antigen presentation, activation and co-stimulation of T cells, for mounting effective antitumour immunity. We describe how the tumour vasculature limits antitumour T cell responses and how T cell responses could be improved by therapeutic targeting of the TAV. In particular, the use of combination therapies that aim to normalize tumour blood vessels, favourably reprogramme endogenous immunity, and support T cell trafficking, function and persistence will be key to improving clinical responses.
    DOI:  https://doi.org/10.1038/s41577-025-01187-w
  3. J Cell Biol. 2025 Aug 04. pii: e202409103. [Epub ahead of print]224(8):
    Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.
    Bobby White, Zhenyi Wang, Matthew Dean, Johanna Michl, Natalia Nieora, Sarah Flannery, Iolanda Vendrell, Roman Fischer, Alzbeta Hulikova, Pawel Swietach.
      Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, notably enhanced fermentation that acidifies poorly perfused tissues and may eventually become more damaging than adaptive. How pH feeds back on hypoxic signaling is unclear but critical to investigate because acidosis and hypoxia are mechanistically coupled in diffusion-limited settings, such as tumors. Here, we examined the pH sensitivity of hypoxic signaling in colorectal cancer cells that can survive acidosis. HIF-1α stabilization under acidotic hypoxia was transient, declining over 48 h. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (e.g., CA9, PDK1), but these did not reflect a proteome-wide downregulation. Enrichment analyses suggested a role for lysosomal degradation. Indeed, HIF-1α destabilization was blocked by inactivating lysosomes, but not proteasome inhibitors. Acidotic hypoxia stimulated lysosomal activity and autophagy via mammalian target of rapamycin complex I (mTORC1), resulting in HIF-1α degradation. This response protects cells from excessive acidification by unchecked fermentation. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling.
    DOI:  https://doi.org/10.1083/jcb.202409103
  4. J Immunother Cancer. 2025 Jun 24. pii: e011036. [Epub ahead of print]13(6):
    Ectopic expression of GDF15 in cancer-associated fibroblasts enhances melanoma immunosuppression via the GFRAL/RET cascade.
    Zhijie Zhao, Huabao Cai, Wenyang Nie, Xiaojing Wang, Zhenzhen Zhao, Fu Zhao, Yisheng Chen, Zhiwen Luo, Zhiheng Lin, Li Lin, Yantao Ding.
       BACKGROUND: A key aspect of tumor biology is the involvement of cancer-associated fibroblasts (CAFs) in shaping the immunosuppressive microenvironment. However, the dynamic and complex key roles of CAFs in the melanoma immune microenvironment have not been elucidated.
    METHODS: The CAFs landscape in melanoma was characterized using single-cell RNA-seq and spatial transcriptomics. Molecular dynamics simulations were employed to validate the interactions between CAFs and melanoma cells. Bulk RNA-seq was used to establish a prognostic model. To validate the expression of key targets, western blotting, quantitative real-time PCR, and ELISA were performed. The molecular interactions were confirmed via co-immunoprecipitation, chromatin immunoprecipitation, and luciferase gene reporter assays. In-depth molecular mechanisms were explored using lentiviral transfection, cell co-culture experiments, recombinant protein rescue experiments, flow cytometry, knockout mice, and Cre-loxP system mice.
    RESULTS: This study identified a unique group of CAFs expressing high levels of growth differentiation factor 15 (GDF15). The paracrine secretion of GDF15 was regulated by the transcription factor FOXP1, which subsequently binds to the TGFBR2 receptor on melanoma cells, driving their proliferation and metastatic capacity. In addition, CAFs-derived GDF15 interacts with the GFRAL receptor on melanoma cells, thereby promoting RET phosphorylation and triggering downstream signaling axes, inducing increased tumor cell stemness and secretion of inflammatory factors CCL18 and TGF-β. This cascade reaction ultimately induces macrophage polarization to the immunosuppressive M2 phenotype, assists in the establishment of an immunosuppressive microenvironment, and leads to accelerated melanoma lung metastasis.
    CONCLUSION: By integrating single-cell RNA-seq, spatial transcriptomics, bulk RNA-seq, molecular dynamics simulation and complete experimental design, this study comprehensively characterized that ectopic expression of CAFs-derived GDF15 can act as an accomplice in melanoma progression by inducing increased tumor cell stemness and macrophage M2 polarization, reshaping the immune landscape of melanoma, and providing new ideas and new targets for precision immunotherapy of melanoma.
    Keywords:  Biomarker; Immunosuppression; Macrophages; Melanoma; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2024-011036
  5. Nat Cancer. 2025 Jun 27.
    Vascular collapse leads to muscle wasting in cancer cachexia.
    Denis C Guttridge, Teresa A Zimmers.
      
    DOI:  https://doi.org/10.1038/s43018-025-01002-4
  6. J Cachexia Sarcopenia Muscle. 2025 Jun;16(3): e13847
    Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting-Induced Proteolysis.
    Meritxell Espino-Guarch, Susie Shih Yin Huang, Clara Vilches, Esther Prat, Rana El Nahas, Ghalia Missous, Susanna Bodoy, Abbirami Sathappan, Mohammad Ameen Al-Aghbar, Clara Mayayo, Montse Olivé, Silvia Busquets-Rius, David Sebastián, Antonio Zorzano, Manuel Palacin, Nicholas van Panhuys, Virginia Nunes.
       BACKGROUND: The neutral amino acid transporter SLC7A8 (LAT2) has been described as a key regulator of metabolic adaptation. LAT2 mutations in human populations have been linked to the early onset of age-related hearing loss and cataract growth. As LAT2 was previously found to be highly expressed in skeletal muscle, here we characterised its role in the regulation of skeletal muscle amino acid flux and metabolic adaptation to fasting.
    METHODS: Wild-type (WT) and LAT2 knock-out (LAT2KO) mice were exposed to short- and long-periods of fasting (16 and 48 h). The impact of the absence of LAT2 on amino acid content, gene expression, proteolysis activity, muscle tone, and histology was measured. To characterise the impact on muscle degradation, we tested LAT2 KO mice in cancer-associated cachexia, streptozocin-induced Type-1 diabetes, and ageing models.
    RESULTS: LAT2KO mice experienced a notable reduction in body weight during fasting (WT:14% and LAT2KO:18%, p = 0.02), with a greater reduction in fat mass (0.5-fold, p = 0.013) and a higher relative retention of muscle mass (1.3-fold, p = 0.0003) compared with WT. The absence of LAT2 led to increased intramuscular glutamine (Gln) accumulation (6.3-fold, p < 0.0001), accompanied by a reduction in skeletal muscle proteolysis during fasting (0.61-fold, p = 0.0004) primarily due to decreased proteasomal and autophagic activity (0.45-fold, p = 0.016 and 0.7-fold, p = 0.002, respectively). Ex vivo incubation of LAT2KO muscle with rapamycin recovered proteolysis function, demonstrating a mTORC1-dependent pathway. Decreased proteolysis in LAT2KO animals was associated with increased mTORC1 translocation to the lysosome (mTORC1-Lamp1 colocalization in fasted LAT2KO muscles was 1.23-fold, p < 0.0001). Of the three muscle loss models tested, differences were observed only during ageing. Young LAT2KO mice (3 M) exhibited muscle tone and MurF1 expression levels comparable to those of older WT mice (12 M) (0.44-fold, p = 0.02 and 0.48-fold, p = 0.04, respectively).
    CONCLUSION: LAT2 has a critical role in regulating Gln efflux from skeletal muscle. The absence of LAT2 led to elevated intracellular Gln levels, impairing muscle proteolysis by inducing mTORC1 recruitment to the lysosome. Further, chronic Gln accumulation and decreased proteolysis were found to induce the early onset of an age-related muscle phenotype.
    Keywords:  LAT2; ageing; glutamine; mTORC1; proteolysis; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13847
  7. Sci China Life Sci. 2025 Jun 25.
    ULK1-dependent phosphorylation of OGT instructs the tumorigenicity of O-GlcNAcylation.
    Zhuan Lv, Qingen Da, Yumiao Li, Aiyun Yuan, Guangcan Shao, Xiaoxuan Lu, Yue Wang, Xuefang Zhang, Jingjing Liu, Meng-Qiu Dong, Yuanyuan Ruan, Chen Wu, Kunfu Ouyang, Jing Li.
      Investigations from the last four decades have correlated high O-linked N-acetylglucosamine (O-GlcNAc) levels with various cancer types, but it is not known how OGT responds to diverse nutrients to finetune cellular O-GlcNAcylation levels. Herein we identified a critical OGT phosphorylation site by unc-51 like autophagy activating kinase 1 (ULK1) under glucose depletion. First, we demonstrated that glucose levels modulate the interaction between OGT and ULK1 and cellular O-GlcNAcylation levels. Low glucose induces high O-GlcNAcylation, which could be reversed by ULK1 inhibition. Then, using mass spectrometry, we showed that ULK1 phosphorylates OGT at Ser576 and stabilizes OGT. Further biochemical experiments revealed that Ser576 phosphorylation inhibits Lys604 ubiquitination by stimulating OGT binding with BAP1, a de-ubiquitinase for OGT. Strikingly, using the OGTS576A knock-in cells, we found that in mouse xenograft models OGT-S576A completely abolishes the tumorigenicity of OGT, probably due to low O-GlcNAcylation. In sum, we found that ULK1 phosphorylates OGT at Ser-576 under glucose deprivation, which stabilizes OGT by promoting OGT-BAP1 association and is pivotal for O-GlcNAcylation levels and tumorigenesis. As low glucose is often associated with tumor progression, our work not only unearths a key mechanism of how OGT is regulated by glucose levels, but also offers new therapeutic opportunities targeting OGT.
    Keywords:  BAP1; O-GlcNAcylation; O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT); ULK1; glucose
    DOI:  https://doi.org/10.1007/s11427-024-2924-6
  8. J Mol Med (Berl). 2025 Jun 21.
    ATF4 in proximal tubules modulates kidney function and modifies the metabolome.
    Yuling Chi, Eduardo Mere Del Aguila, Tuo Zhang, Charles D Warren, Helen R Hoxie, Qiuying Chen, Steven S Gross, Jacob B Geri, David M Nanus, Lorraine J Gudas.
      Activating transcription factor 4 (ATF4) is a transcription factor that mediates the response to stress at the cellular, tissue, and organism level. We deleted the gene encoding ATF4 in the proximal tubules of the mouse kidney by using a temporal and cell type-specific approach. We show that ATF4 plays a major role in regulating the transcriptome and proteome, which, in turn, influences the metabolome and kidney functions. Genome-wide transcriptomics and single-plot, solid-phase-enhanced sample preparation (SP3)-proteomics studies reveal that ATF4 deletion changes more than 30% of transcripts and, similarly, corresponding proteins in the proximal tubules. Gene Set Enrichment Analysis indicates major changes in transporters, including amino acid transporters. Metabolomic analyses show that these changes in transporters are associated with altered profiles of amino acids in the blood, kidney, and urine. Stable isotope glutamine tracing in primary tubule cells isolated from kidney cortices confirms that ATF4 regulates glutamine transport and metabolism. We suggest that even in the absence of additional stresses, such as kidney injury, ATF4 in the proximal tubules modulates both retention of specific nutrients and excretion of catabolic products like creatinine to maintain normal kidney function. KEY MESSAGES: Activating transcription factor 4 (ATF4) deletion changed more than 30% of genome-wide transcripts and corresponding proteins in the proximal tubules. One set of the profound changes occurred in amino acid transporters and Slc22 family transporters. Changes in transporters were accompanied by altered profiles of amino acids and wastes in the blood, kidney, and urine. ATF4 in the kidney proximal tubules plays a key role in regulating both the reabsorption of nutrients and the excretion of wastes.
    Keywords:  Activating transcription factor 4 (ATF4); Kidney proximal tubules; Metabolomics; Proteomics; Transcriptomics; Transporters
    DOI:  https://doi.org/10.1007/s00109-025-02559-4
  9. Front Immunol. 2025 ;16 1593834
    Beyond boundaries: exploring the role of extracellular vesicles in organ-specific metastasis in solid tumors.
    Goutham Nidhi, Vikas Yadav, Tejveer Singh, Deepika Sharma, Monica Bohot, Shakti Ranjan Satapathy.
      Extracellular vesicles (EVs) have been identified as important mediators of cancer metastasis, especially in the establishment of organ-specific metastatic niches. These membranous vesicles secreted by tumor cells release diverse bioactive cargo, including proteins, nucleic acids, and lipids, thereby allowing for intercellular communication and microenvironment modulation. Recent evidence demonstrates that EVs can also contribute to the formation of pre-metastatic niches by reprogramming immune cells, modifying the stromal environment, and inducing epithelial-mesenchymal transition (EMT) to promote metastatic colonization. In this review, we describe the molecular mechanism of organotropic metastasis orchestrated by EVs, with special emphasis on immune modulation and tumor microenvironment reprogramming. We also explore the potential of EVs as biomarkers for early detection of metastasis and as potential therapeutic targets for combating metastatic progression. Dissociating EV species and their influence on tumor dissemination will undoubtedly pave the way for implementing novel anti-cancer strategies to intercept tumor dissemination at its very early stages.
    Keywords:  EMT; cancer; exosome; extracellular vesicles; metastasis
    DOI:  https://doi.org/10.3389/fimmu.2025.1593834
  10. Cell Metab. 2025 Jun 19. pii: S1550-4131(25)00294-3. [Epub ahead of print]
    RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation.
    Zezhao Chen, Xiaosong Gu, Hongbo Chen, Huijing Zhang, Jianping Liu, Xiaohua Yang, Yuping Cai, Mengmeng Zhang, Lingjie Yan, Yuanxin Yang, Bing Shan, Zheng-Jiang Zhu, Yixiao Zhang, Jinyang Gu, Daichao Xu.
      The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S-adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans-activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.
    Keywords:  PRMT5; RIPK1; S-adenosylmethionine; TNF signaling; apoptosis; death domain; inflammation; methionine; methylation; one-carbon metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.014
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