bims-stacyt 2025-07-13 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–07–13
thirteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

GDF15: from biomarker to target in cancer cachexia.
Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.
The HIF axes in cancer: angiogenesis, metabolism, and immune-modulation.
Hypoxia promotes the generation of a versican-rich extracellular matrix by human coronary artery endothelial cells.
ANGPTL3 orchestrates hepatic fructose sensing and metabolism.
Energy stress and adaptation strategy of tumor cells in different microenvironments: from primary tumors to distant metastases.
Fucosterol Promotes Browning in Mouse 3T3-L1 Adipocytes Through HO-1/Nrf2 and AMPK Pathways.
Endoplasmic Reticulum Stress-Driven Nucleotide Catabolism Fuels Prostate Cancer.
Paradoxical regulation of IGF2 in promoting lipid metabolism in adipose tissues.
Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer.
Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.
Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis.
Metabolic reprogramming of tumor-associated macrophages via adenosine-A2AR signaling drives cross-resistance in non-small cell lung cancer.

Trends Cancer. 2025 Jul 09. pii: S2405-8033(25)00150-5. [Epub ahead of print]

GDF15: from biomarker to target in cancer cachexia.

Max Hüllwegen, Maximilian Kleinert, Stephan von Haehling, Andreas Fischer.

  Most patients with advanced cancer suffer from cachexia, a complex metabolic disorder characterized by unintentional body weight loss that diminishes their quality of life and reduces the effectiveness of therapies. Currently, effective treatments for cachexia remain elusive. Growth differentiation factor 15 (GDF15) is a nonspecific blood biomarker of cancer, hyperemesis gravidarum, and various chronic diseases. GDF15 acts through GDNF family receptor α-like (GFRAL) receptors in the hindbrain to influence food intake, nausea, body weight, and insulin sensitivity. In this review we synthesize the current literature on the role of GDF15 in regulating metabolism and immunosuppression, and elucidate how these processes impact on cancer progression. We highlight recent clinical trials demonstrating that targeting GDF15 can overcome resistance to immunotherapy and increase physical activity, appetite, and weight gain in cancer patients.

Keywords:  GDF15; biomarker; cachexia; cancer; immunosuppression; metabolism

DOI:  https://doi.org/10.1016/j.trecan.2025.06.007
Sci Adv. 2025 Jul 11. 11(28): eadw1883

Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.

Shruthi Krishnan, Ana Lima, Sizhe Tan, Ying Thong Low, Salvador Perez Montero, Aida Di Gregorio, Adrian Perez Barreto, Sarah Bowling, Karen Vousden, Tristan A Rodriguez.

Cell competition is a conserved fitness quality control that eliminates cells that are less fit than their neighbors. How winner cells induce the elimination of losers is poorly understood. We tackle this question by studying the onset of embryonic differentiation in mice, where cell competition eliminates 35% of embryonic cells. These loser cells have mitochondrial dysfunction, which we show causes amino acid deprivation and activation of the integrated stress response (ISR), a pathway essential for their survival. We demonstrate that l-proline is a key amino acid sensed by the ISR and that proline represses the ISR and drives their elimination. These results indicate that cell competition acts as a previously unidentified tissue-sparing mechanism, regulated by the availability of extracellular amino acids, that allows for the elimination of dysfunctional cells when amino acids are plentiful but ensures their survival in nutrient-poor environments.

DOI: https://doi.org/10.1126/sciadv.adw1883
Trends Biochem Sci. 2025 Jul 09. pii: S0968-0004(25)00135-5. [Epub ahead of print]

The HIF axes in cancer: angiogenesis, metabolism, and immune-modulation.

Karen Acuña-Pilarte, Mei Yee Koh.

  The hypoxia-inducible factors (HIFs) are central transcriptional mediators of the cellular response to hypoxia. HIF activation typically drives a physiologically beneficial adaptive response to hypoxia. However, within solid tumors, the HIF-driven adaptation to hypoxia results in alterations within major cancer cell signaling axes, including those regulating angiogenesis, metabolism, and immune modulation, which profoundly impact tumor progression. This review describes established and recent findings of the role of HIFs in the regulation of these major axes, and the impact of the 'HIF axes' on tumor progression and response to therapy. Current and emerging therapies targeting these axes will also be discussed.

Keywords:  hypoxia; hypoxia-inducible factor (HIF); metabolic reprogramming; solid tumors; therapeutics targeting; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tibs.2025.06.005
J Biol Chem. 2025 Jul 05. pii: S0021-9258(25)02309-9. [Epub ahead of print] 110459

Hypoxia promotes the generation of a versican-rich extracellular matrix by human coronary artery endothelial cells.

Sara M Jørgensen, Song Huang, Lasse G Lorentzen, Fallen K Y Teoh, Richard Karlsson, John R Harkness, Rebecca L Miller, Michael J Davies, Christine Y Chuang.

  Normal endothelial cell (EC) function is essential for vascular wall homeostasis, whereas dysfunction increases the risk of cardiovascular disease. Low O2 tension (hypoxia) promotes EC dysfunction and the formation of atherosclerotic plaques. Increasing evidence suggests that hypoxia drives extracellular matrix (ECM) remodeling, an established contributing factor in atherosclerosis. However, the effects of hypoxia on ECs and associated ECM proteins are poorly understood. The aim of this study was to investigate whether the culture of human coronary artery ECs under 1% O2 (hypoxia) alters the ECM generated by these cells, and if this affects HCAEC function. Exposure of HCAECs to 1% O2 resulted in a hypoxic response (HIF-1α stabilization), dysfunction (increased oxidant formation and decreased eNOS), and inflammatory activation (increased IL-6 and ICAM-1 expression). Proteomic analysis of HCAECs cultured under 1% and 20% O2 for 7 days revealed many hypoxia-induced changes to extracellular proteins, particularly increased versican, a key ECM proteoglycan. Increased versican expression and deposition was confirmed at the mRNA and protein level, along with its glycosaminoglycan (chondroitin sulfate) chains and particularly 6-O-sulfated species. This versican-rich ECM showed increased hyaluronan binding and decreased cell adhesiveness, but attached cells proliferated at a greater rate. The generation of a versican-rich ECM under 1% O2 provides a link between hypoxia and atherosclerosis, since versican is reported to accumulate in plaques, where it binds and retains low-density lipoproteins and is involved in inflammatory cell recruitment, thereby potentiating low-density lipoprotein modification and the accumulation of lipid-laden (foam) cells.

Keywords:  endothelial cell; extracellular matrix; hypoxia; proteomics; reactive oxygen species; versican

DOI:  https://doi.org/10.1016/j.jbc.2025.110459
Cell Rep. 2025 Jul 09. pii: S2211-1247(25)00733-8. [Epub ahead of print]44(7): 115962

ANGPTL3 orchestrates hepatic fructose sensing and metabolism.

Meng Zhao, Karen Y Linde-Garelli, Zeyuan Zhang, David Toomer, Saranya C Reghupaty, John Isaiah Jimenez, Laetitia Coassolo, Lianna W Wat, Daniel Fernandez, Katrin J Svensson.

  Fructose metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but the regulatory mechanisms governing fructose uptake remain poorly understood. Here, we demonstrate that MASLD livers exhibit increased uptake of fructose-derived carbons compared to healthy livers and identify that the MASLD hepatocyte secretome can increase fructose metabolism. By performing fractionation and untargeted proteomics, we uncover a role for Angiopoietin-like 3 (ANGPTL3) as a regulator of hepatic fructose metabolism, independent of its role as a lipoprotein lipase (LPL) inhibitor. Circulating ANGPTL3 levels increase in response to fructose exposure, consistent with an action as a fructose sensor. Angptl3 knockdown in the liver resulted in a significant reduction in the uptake of hepatic fructose metabolites in vivo and downregulation of the facilitative hepatic fructose transporter slc2a8 (GLUT8) and fructolysis enzymes. This work demonstrates the existence of extracellular control of hepatic fructose metabolism through ANGPTL3.

Keywords:  ANGPTL3; CP: Metabolism; MASLD; fructolysis; fructose

DOI:  https://doi.org/10.1016/j.celrep.2025.115962
Acta Biochim Biophys Sin (Shanghai). 2025 Jul 04.

Energy stress and adaptation strategy of tumor cells in different microenvironments: from primary tumors to distant metastases.

Mingzhe Xu, Junjie Fei, Zhi-Xiong Xiao, Yong Yi.

  Since the Warburg effect was first described in the 1920s, tumor energy metabolism has been a central focus of cancer research, emerging as a potential therapeutic target. The tumor microenvironment-including blood vessels, immune cells, stromal components, and other cell types-profoundly influences tumor cell metabolism. Variations in energy supply, oxygen availability, nutrient composition, and the accumulation of metabolic waste across different microenvironments challenge tumor cell survival and progression. In response, tumor cells adapt through flexible regulation and reprogramming of metabolic pathways. Although recent studies have explored metabolic adaptation mechanisms in various tumor microenvironments, the full spectrum from primary tumors to distant metastases remains unexplored. This review summarizes energy stress and adaptation maneuvers in tumor cells across different stages of tumor progression and offers a new perspective for comprehensive research to explore therapeutic strategies targeting tumor metabolism.

Keywords:  energy stress; metabolic reprogramming; tumor cell survival; tumor microenvironment

DOI:  https://doi.org/10.3724/abbs.2025106
Biofactors. 2025 Jul-Aug;51(4):51(4): e70035

Fucosterol Promotes Browning in Mouse 3T3-L1 Adipocytes Through HO-1/Nrf2 and AMPK Pathways.

Indyaswan T Suryaningtyas, Won-Kyo Jung, Jae-Young Je.

  Browning of white adipose tissue offers a promising strategy to manage obesity by enhancing thermogenesis and lipid oxidation. Although fucosterol, a phytosterol found in brown seaweeds, has been recognized for its antioxidant and metabolic benefits, its ability to trigger browning has not been previously reported. In this study, we demonstrate for the first time that fucosterol induces adipocyte browning in 3T3-L1 cells. Treatment with fucosterol (10-50 μM) during adipogenic differentiation suppressed lipid accumulation and downregulated adipogenic transcription factors (PPARγ, C/EBPα, SREBP-1), while enhancing lipolysis via increased phosphorylation of HSL and AMPK. Critically, browning markers PRDM16, PGC1α, and UCP1 were robustly upregulated in a dose-dependent manner. Fucosterol also activated the Nrf2/HO-1 antioxidant pathway, as evidenced by increased HO-1 expression and Nrf2 nuclear translocation. Pharmacological inhibition of HO-1 or AMPK reversed these effects, confirming their essential role in fucosterol-induced thermogenic remodeling. Interestingly, despite activation of p38 and ERK MAPKs-often linked to stress signaling-fucosterol reduced pro-inflammatory cytokine levels (IL-6, IL-1β, TNF-α) and elevated antioxidant enzymes (SOD, GPx, CAT), suggesting a non-inflammatory metabolic adaptation. These findings reveal a previously uncharacterized function of fucosterol in promoting adipocyte browning, driven by HO-1/Nrf2 and AMPK pathways, with potential relevance for therapeutic strategies targeting obesity.

Keywords:  AMPK; HO‐1/Nrf2 pathway; adipocyte browning; fucosterol; lipid metabolism

DOI:  https://doi.org/10.1002/biof.70035
Cancer Lett. 2025 Jul 03. pii: S0304-3835(25)00456-2. [Epub ahead of print] 217888

Endoplasmic Reticulum Stress-Driven Nucleotide Catabolism Fuels Prostate Cancer.

Ke Deng, Nora Pällmann, Marte Livgård, Wanja Kildal, Manohar Pradhan, Ladan Fazli, Paul S Rennie, Yang Jin, Fahri Saatcioglu, Omer Kuzu.

Endoplasmic reticulum (ER) stress is a critical regulator of cancer cell metabolism and survival. In this study, we elucidate the coordinated roles of two key ER stress mediators, Activating Transcription Factor 4 (ATF4) and X-box Binding Protein 1 spliced (XBP1s), in regulating purine homeostasis in prostate cancer (PCa) cells. We demonstrate that ATF4 directly upregulates Molybdenum Cofactor Sulfurase (MOCOS), a key enzyme in purine catabolism, while XBP1s induces the expression of xanthine dehydrogenase (XDH), the principal MOCOS target in this pathway. Knockdown of MOCOS significantly impairs PCa cell proliferation as well as prostatosphere and colony formation in vitro and inhibits tumor growth in preclinical mouse models of PCa. Mechanistically, MOCOS suppression leads to purine accumulation, disrupts pyrimidine synthesis, and causes nucleotide imbalance, resulting in replication fork stalling. This imbalance is also accompanied by a compromised glutathione-mediated antioxidant response, rendering the cells more susceptible to DNA damage. Importantly, targeting XDH, either genetically or biochemically, also significantly hinders PCa cell growth. Collectively, our data highlight the pivotal role of ER stress-mediated purine homeostasis in sustaining PCa cell growth.

DOI: https://doi.org/10.1016/j.canlet.2025.217888
Commun Biol. 2025 Jul 09. 8(1): 1026

Paradoxical regulation of IGF2 in promoting lipid metabolism in adipose tissues.

Caiping Zhou, Weiwei Gui, Weifen Zhu, Hanxin Zhao, Dingting Wu, Fang Wu, Gangliang Wang, Xihua Lin.

Metabolic diseases such as diabetes, obesity, and dyslipidemia pose major public health challenges globally. While the insulin-like growth factor 2 (IGF2) gene is known to be involved in various physiological processes, its precise role in lipid metabolism is still not well understood. Here we show that IGF2 plays a crucial role in regulating lipid metabolism in adipose tissues and is linked to metabolic syndrome (MetS). Multiple SNP loci in the IGF2 gene were significantly associated with BMI, HbA1c, and diabetes. Insufficient or excessive expression of IGF2 was identified as a risk factor for hyperlipidemia, low HDL-c, and central obesity in MetS. Enhanced IGF2 expression stimulated adipogenesis and lipid accumulation, whereas IGF2 knockdown hindered lipolysis, exacerbating ectopic lipid accumulation and insulin resistance. Activation of the PI3K/Akt pathway through IGF1R in IGF2 excess or INSR in conditions of IGF2 scarcity, along with inhibition of AMPK, implies a common downstream process that favors lipid accumulation and metabolic reprogramming in adipocytes. This research provides valuable insights into the mechanisms underlying IGF2's impact on lipid metabolism and has the potential to guide future therapeutic strategies for metabolic diseases.

DOI: https://doi.org/10.1038/s42003-025-08458-1
Front Immunol. 2025 ;16 1618439

Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer.

Zhengfang Liang, Fengwei Nong, Zhenjie Li, Runmin Chen, Haoxu Zhao, Yongping Huang.

   Background: Bladder cancer (BLCA) remains heavily dependent on bacillus Calmette-Guérin (BCG) therapy due to the profound heterogeneity of its tumor microenvironment (TME) and deregulated metabolic landscapes. Taurine metabolism (TM) is a pivotal axis in BLCA, exhibiting dual roles in tumor progression and immune evasion. Deciphering the molecular mechanisms by which TM reprogramming fosters immunosuppression is imperative for advancing BLCA immunotherapy.
Methods: This study employed an integrative approach combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk transcriptome analyses to unravel taurine metabolic dysregulation in the BLCA TME. Computational frameworks such as Seurat and Monocle 3 were used to characterize cellular subpopulations, reconstruct differentiation trajectories, and model intercellular signaling networks. A taurine metabolic dysregulation index (TMs) was developed using TCGA cohorts, with survival modeling and machine learning methodologies deployed to assess its prognostic utility. Immuno-infiltration patterns and immunotherapeutic responsiveness were quantified via algorithms including ESTIMATE and TIDE. Mechanistic validation was achieved through co-culture systems.
Results: ScRNA-seq profiling revealed significant perturbations in TM scores across epithelial cells, fibroblasts, and macrophages within the BLCA TME. High TMs clusters were enriched for Notch signaling and EGFR tyrosine kinase inhibitor resistance pathways. Spatial transcriptomics analyses highlighted spatiotemporal heterogeneity in taurine metabolic gene expression. The TMs index emerged as an independent prognostic biomarker, with high TMs patients demonstrating significantly shorter overall survival and synergistic prognostic deterioration in the context of high tumor mutational burden (TMB). High TMs tumors exhibited enrichment of immunosuppressive cell compartments and elevated immune checkpoint molecule expression. Mechanistically, FAAH knockdown in cancer-associated fibroblasts (CAFs) attenuated co-cultured BLCA cell viability, potentially mediated by CCL15 secretion.
Conclusion: This study establishes that taurine metabolic dysregulation reconfigures intercellular signaling within the BLCA TME, driving immunosuppression and tumor progression. The TMs framework enables robust patient stratification and provides a mechanistic rationale for therapeutic strategies targeting TM in conjunction with immune checkpoint inhibitors, thus paving the way for advanced precision medicine approaches in BLCA.

Keywords:  CAFs; anti-PD-1; bladder cancer; spatial transcriptomics; taurine

DOI:  https://doi.org/10.3389/fimmu.2025.1618439
Adv Sci (Weinh). 2025 Jul 10. e13084

Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.

Yun Xu, Shumin Li, Jiaji Wu, Shumin Xu, Mo Shen, Chenyang Wang, Lundqvist Andreas, Jianghao Yu, Zhiyong Xu, Yueli Shi, Nana Liu, Yunke Yang, Jiangnan Zhao, Ying Yang, Pingli Wang, Peng Yi, Jin Cheng, Junhui Sun, Mengshu Li, Peng Xiao, Kai Wang.

  Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has shown promising therapeutic effects in the treatment of lung cancer, the overall efficacy of PD-1/PD-L1 inhibitors is only 20%-30%. Thus, more effective combination therapies are needed. This study finds that cystine and cysteine levels in tumor tissues of lung cancer patients are significantly higher than adjacent non-tumor tissues. Cystine deficiency polarizes macrophages toward an M1 phenotype, secreting more TNF-α, CXCL9, and CXCL10. However, using a cystine-free diet marginally reduces the development of lung cancer in vivo. A cystine-free diet slightly reduces lung cancer progression in vivo. Further studies show that cystine deprivation or erastin-mediated transport inhibition increased PD-L1 expression in macrophages both in vitro and in vivo. Combining a cystine-free diet or IKE injection with PD-L1 antibody treatment significantly inhibited subcutaneous tumor growth in mice. Mechanistic studies indicat that cystine deficiency-induced GSH depletion activates NF-κB in macrophages by reducing its glutathionylation. This effect can be reversed by replenishing GSH or using an NF-κB inhibitor. At the same time, lung cancer patients with better responses to immunotherapy are found to have lower serum GSH levels. These findings suggest that targeting cystine metabolism combined with PD-L1 inhibition is a promising therapeutic strategy.

Keywords:  PD‐L1; cystine; immunotherapy; lung cancer; macrophage polarization; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202413084
Cancer Gene Ther. 2025 Jul 10.

Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis.

Verra M Ngwa, Yoonha Hwang, Wenqiang Song, Deanna N Edwards, Jin Chen.

Targeted therapies have improved survival for lung adenocarcinoma patients. However, similar advances are lacking for lung squamous carcinoma (LUSC). Advances in immunotherapy have shown some promise, but the overall response rate remains low in LUSC. Here, we demonstrate that the mTORC2 signaling pathway represents an actionable target in LUSC to improve anti-tumor immune responses. We show that genetic alterations affecting the mTORC2 pathway are common among patients with LUSC tumors, and targeting mTORC2 reduces LUSC tumor growth in mouse models. Transcriptomics reveal that mTORC2-deficient LUSC cells exhibit reduced expression of glycolytic and hypoxia-related genes. In agreement, loss of mTORC2 signaling decreases lactate levels in tumor-interstitial fluid, creating reduced acidity within the tumor microenvironment. Interestingly, mTORC2-deficient LUSC cells also exhibited reduced expression of the pH-sensitive VISTA ligand PSGL-1 in a HIF-2α dependent mechanism. LUSC patients, but not those with LUAD, display a positive correlation in expression between HIF-2α and PSGL-1, suggesting a distinct association among mTORC2, HIF-2α, and immune responses in LUSC. Indeed, mTORC2 loss-of-function enhanced CD8+ T cell activation in tumors, while use of anti-VISTA immunotherapy reduced LUSC tumor burden only in the presence of intact mTORC2 signaling. Collectively, these data describe an important role of mTORC2 signaling in LUSC tumors and demonstrate the therapeutic potential of targeting the mTORC2/PSGL-1/VISTA axis in patients that are non-responsive to current therapies.

DOI: https://doi.org/10.1038/s41417-025-00934-4
Drug Resist Updat. 2025 Jun 30. pii: S1368-7646(25)00075-5. [Epub ahead of print]82 101272

Metabolic reprogramming of tumor-associated macrophages via adenosine-A2AR signaling drives cross-resistance in non-small cell lung cancer.

Wen Ding, Jianshan Mo, Yingxue Su, Qiyi Zhang, Danyuan Sun, Xiangchao Yao, Guopin Liu, Jiangling Ye, Yanle Wu, Menghan Xue, Peibin Yue, Jinjian Lu, Jian Zhang, Yanyu Shi, Wenhao Hu, Kai Zhu, Yandong Wang, Xiaolei Zhang.

  Immunosuppression within the tumor microenvironment (TME) is frequently associated with chemoresistance. However, the mechanisms by which chemoresistance promotes immune evasion and impairs subsequent immunotherapy remain poorly understood, underscoring the urgent need for novel therapeutic strategies to counteract these effects. In this study, we observed that tumors exhibit cross-resistance to immunotherapy following chemoresistance in a non-small cell lung cancer (NSCLC) mouse model. The aberrant accumulation of tumor-associated macrophages (TAMs) and extracellular adenosine (Ado) were identified as mediators of immunosuppression, fostering cross-resistance to immunotherapy in the context of chemoresistance. Mechanistically, selective activation of the Ado/A2AR signaling pathway induced metabolic reprogramming of TAMs, thereby creating an immunosuppressive niche in cross-resistant NSCLC. Based on these findings, we designed a novel selective A2AR inhibitor DL082 and explored its therapeutic potential for treating cross-resistant NSCLC. The combination of DL082 with an anti-PD-L1 antibody significantly enhanced immune activation and inhibited tumor progression in cross-resistant NSCLC. These findings elucidate the specific mechanisms underlying cross-resistance between chemotherapy and immunotherapy in NSCLC and propose targeting the Ado-TAM axis as a potential strategy for overcoming resistance in NSCLC therapy.

Keywords:  Adenosine; Cross-resistance; Immunotherapy; NSCLC; TAM

DOI:  https://doi.org/10.1016/j.drup.2025.101272