bims-stacyt 2025-09-28 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–09–28
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

GCN2 enhances host survival and drives eIF2α phosphorylation during mouse adenovirus type 1 infection.
Identification of Amino Acids That Regulate Angiogenesis and Alter Pathogenesis of a Mouse Model of Choroidal Neovascularization.
Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.
Intra-tumoral hypoxia promotes CD8+ T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.
Hypoxia-Driven Extracellular Vesicles Promote Pro-Metastatic Signalling in LNCaP Cells via Wnt and EMT Pathways.
Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study.
Fractalkine is a key player in skeletal muscle metabolism and pathophysiology.

J Virol. 2025 Sep 24. e0128825

GCN2 enhances host survival and drives eIF2α phosphorylation during mouse adenovirus type 1 infection.

Luiza A Castro Jorge, Daniel F Edwards, Rosario Labastida, Danielle E Goodman, Estela A Pereira, Oded Foreman, Katherine R Spindler.

  The integrated stress response (ISR) is a cellular signaling pathway that reduces protein synthesis in the face of cellular stress, including viral infection. Two eukaryotic initiation factor 2α (eIF2α) kinases, protein kinase R (PKR) and general control nonderepressible 2 (GCN2), are commonly activated during viral infections. Mouse adenovirus type 1 (MAV-1) infection leads to a steep reduction of PKR levels by proteasomal degradation. We assayed whether GCN2, a sensor of amino acid starvation and UV damage, plays a role in the ISR to MAV-1 infection. There was more phosphorylated GCN2 in MAV-1-infected cells, and its activation was dependent on virus replication since UV-inactivated virus was not able to increase the phosphorylation of GCN2. Infected Eif2ak4tm1.2Dron mice (designated here Gcn2-/- mice) had lower survival than wild-type (WT) mice, but results indicated that this was not due to increased viral replication. Both Gcn2-/- and WT mice developed multifocal brain parenchymal microhemorrhages during infection. While Gcn2-/- animals had more lesions, their higher mortality is likely not due to the microhemorrhages alone. Cytokine RNA and protein assays of WT and Gcn2-/- mice only showed a difference for IL- β levels, which were higher in Gcn2-/- mice. Our results also indicate that of the two eIF2α kinases, PKR and GCN2, GCN2 is the primary inducer of phosphorylated-eIF2α during MAV-1 infection. GCN2 is thus antiviral and contributes to the host response to MAV-1 infection.IMPORTANCECells often respond to viral infection by activation of the host protein kinase R (PKR), part of the integrated stress response (ISR). We show that a second host protein kinase, general control nonderepressible 2 (GCN2), is activated by phosphorylation in response to mouse adenovirus type 1 (MAV-1) infection. Our results indicate GCN2 is antiviral: without it, the mortality in MAV-1-infected mouse is higher. Furthermore, the data show that GCN2, rather than PKR, is the main inducer of eIf2α phosphorylation (and thus the ISR) upon MAV-1 infection. This is consistent with PKR exerting antiviral effects in MAV-1 infections through a pathway independent of eIf2α phosphorylation.

Keywords:  PKR; general control nonderepressible 2; integrated stress response; protein kinase R

DOI:  https://doi.org/10.1128/jvi.01288-25
Nutrients. 2025 Sep 19. pii: 3006. [Epub ahead of print]17(18):

Identification of Amino Acids That Regulate Angiogenesis and Alter Pathogenesis of a Mouse Model of Choroidal Neovascularization.

Chenchen Li, Jiawen Wu, Yingke Zhao, Jing Zhu, Xinyu Zhu, Yan Chen, Jihong Wu.

  Background: Metabolic stress from amino acid (AA) insufficiency is increasingly linked to pathological angiogenesis, but specific essential AA (EAA) roles remain undefined. Neovascular age-related macular degeneration (AMD), a major cause of blindness driven by aberrant ocular neovascularization, has limited efficacy with current VEGFA-targeting therapies. We sought to identify specific EAAs that regulate pathological angiogenesis and dissect their mechanisms to propose new therapeutic strategies. Methods: Human retinal microvascular endothelial cells (HRMVECs) were used to identify angiogenesis-regulating amino acids through systematic EAA screening. The molecular mechanism was investigated using shRNA-mediated knockdown of key stress response regulators (HRI, PKR, PERK, GCN2) and ATF4. Angiogenesis was assessed via tubule formation and migration assays. Therapeutic potential was examined in a laser-induced choroidal neovascularization (CNV) mouse model, evaluated by fluorescein angiography and histomorphometry. Results: Deprivation of methionine, lysine, and threonine potently induced capillary-like tube formation (p < 0.01). Mechanistically, restriction of these three EAAs activated HRI and GCN2 kinases, converging on eIF2α phosphorylation to induce ATF4 and its target VEGFA. Dual, but not single, knockdown of HRI and GCN2 abolished eIF2α-ATF4 signaling and angiogenic responses. Restricting these EAAs exacerbated CNV area in mice. Conclusions: Our findings reveal a coordinated HRI/GCN2-ATF4-VEGFA axis linking EAA scarcity to vascular remodeling, establishing proof-of-concept for targeting this pathway in CNV. This work highlights the therapeutic potential of modulating specific AA availability or targeting the HRI/GCN2-ATF4 axis to treat CNV.

Keywords:  activating transcription factor 4; angiogenesis; choroidal neovascularization; essential amino acid restriction; general control nonderepressible 2; heme-regulated inhibitor

DOI:  https://doi.org/10.3390/nu17183006
Nat Cardiovasc Res. 2025 Sep 24.

Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.

Sumeet A Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L Smythers, Katherine A Blackmore, Louisa Grauvogel, Melanie J Mittenbühler, Melin J Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E Houstis, Hans-Georg Sprenger, Sean J Jurgens, Kiran J Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T Ellinor, Matthias Nahrendorf, Joao A Paulo, Steven P Gygi, Phillip A Dumesic, Aarti Asnani, Krishna G Aragam, Pere Puigserver, Jason D Roh, Bruce M Spiegelman, Anthony Rosenzweig.

Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15.

DOI: https://doi.org/10.1038/s44161-025-00712-3
Immunity. 2025 Sep 25. pii: S1074-7613(25)00414-5. [Epub ahead of print]

Intra-tumoral hypoxia promotes CD8+ T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.

Coral Del Mar Alicea Pauneto, Brian P Riesenberg, Evelyn J Gandy, Andrew S Kennedy, Genevieve T Clutton, Jessica W Hem, Katie E Hurst, Elizabeth G Hunt, Jarred M Green, Brian C Miller, Steven P Angus, Gary L Johnson, Robert J Esther, Jennifer L Guerriero, Peng Gao, David R Soto-Pantoja, Robert L Ferris, Jennifer L Modliszewski, Michael F Coleman, H Kay Chung, J Justin Milner, Stergios J Moschos, R Luke Wiseman, Jessica E Thaxton.

  Metabolic stress in the tumor microenvironment (TME) promotes T cell dysfunction and immune checkpoint inhibitor (ICI) resistance. We examined the contribution of activating transcription factor 4 (ATF4), the central node of the integrated stress response (ISR), to T cell dysfunction in tumors. CD8+ tumor-infiltrating lymphocytes (TILs) in patient samples exhibited chronic ATF4 activity, which was reflected across various tumor models. Hypoxia in the TME imposed chronic ATF4 activity via the ISR kinases. ATF4 overexpression in CD8+ T cells induced metabolic polarity, mitochondrial oxidative stress, and cell death, impairing antitumor immunity. Chronic ATF4 transcriptional activity replicated the terminal exhaustion CD8+ T cell state independent of T cell receptor (TCR) stimulation. Genetic or pharmacologic attenuation of ATF4 reduced mitochondrial oxidative stress and promoted CD8+ TIL viability, enabling response to programmed cell death protein-1 (PD-1) inhibitor therapy and conferring protection from re-emergent disease. Thus, the ISR converges on chronic ATF4 activity in CD8+ TILs as a barrier to ICI response, positioning ISR therapeutics as candidates for immunotherapy.

Keywords:  ATF4; T cell; hypoxia; immunotherapy; integrated stress response; metabolism; mitochondria; tumor microenvironment

DOI:  https://doi.org/10.1016/j.immuni.2025.09.003
Biology (Basel). 2025 Aug 27. pii: 1135. [Epub ahead of print]14(9):

Hypoxia-Driven Extracellular Vesicles Promote Pro-Metastatic Signalling in LNCaP Cells via Wnt and EMT Pathways.

Melissa Santos, Khansa Bukhari, Irem Peker-Eyüboğlu, Igor Kraev, Dafydd Alwyn Dart, Sigrun Lange, Pinar Uysal-Onganer.

  Prostate cancer (PCa) progression is shaped by the tumour microenvironment, where hypoxia promotes aggressiveness and contributes to therapy resistance. Extracellular vesicles (EVs), secreted under hypoxia, can deliver modified bioactive cargo that reprograms recipient cells. This study examined whether EVs from hypoxia-conditioned metastatic PCa cells enhance malignant traits in cancerous and non-tumorigenic prostate cell lines via Wnt signalling and epithelial-mesenchymal transition (EMT). EVs from PC3 cells cultured under hypoxia (1% O2) or normoxia (21% O2) as control were applied to LNCaP (low metastatic potential) and PNT2 (non-tumorigenic) cells. PC3 hypoxia-derived EVs increased HIF-1α, upregulated mesenchymal markers (Vimentin, N-cadherin) and Wnt-related genes (Wnt3A, Wnt5A, Fzd7), and suppressed the epithelial marker E-cadherin. Functional assessment showed that LNCaP cells treated with PC3 hypoxia EVs showed greater motility and invasiveness, and PNT2 cells displayed transcriptomic reprogramming. These findings show that hypoxia-driven EVs can propagate pro-metastatic signalling in less aggressive and normal prostate cells. The findings highlight EVs as a potential therapeutic target in PCa progression.

Keywords:  HIF-1α; Wnt signalling (Wnt); epithelial–mesenchymal transition (EMT); extracellular vesicles (EVs); hypoxia; invasion; prostate cancer; tumour microenvironment

DOI:  https://doi.org/10.3390/biology14091135
Biomolecules. 2025 Aug 26. pii: 1234. [Epub ahead of print]15(9):

Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study.

Marta Tajes, Maria Del Mar Ras-Jiménez, Josefa Girona, Raúl Ramos-Polo, Montse Guardiola, José Manuel García-Pinilla, Josep Ribalta, Marta Cobo-Marcos, Lluís Masana, Javier de Juan-Bagudá, Cândida Fonseca, Cristina Enjuanes, Manuel Vázquez-Carrera, Josep Comin-Colet, Ricardo Rodríguez-Calvo.

  Heart failure (HF), particularly of an ischemic etiology, is steadily increasing worldwide. Non-anemic iron deficiency (ID) is highly prevalent among HF patients, and it has been related to worse outcomes. Growth differentiation factor 15 (GDF15) has been related to atherosclerotic cardiovascular (CV) disease, HF and iron pathophysiology. Nevertheless, the specific potential role of GDF15 in HF patients with ID has not been fully explored. In this cross-sectional study we determined serum GDF15 levels in 60 HF patients with ID from the IRON-PATH II study. The discriminative capacity of GDF15 in logistic regression models for classifying these patients according to ischemic etiology was defined as the primary endpoint. Additionally, relationships between GDF15 levels and impaired right ventricle function, impaired functional capacity and HF were included as secondary endpoints. GDF15 was inversely related to tricuspid annular plane systolic excursion (TAPSE) and the six-minute walking test (6MWT), and positively related to hallmarks of HF [i.e., N-terminal prohormone of brain natriuretic peptide (NT-proBNP)] and other molecules influenced by HF progression [i.e., creatinine and ferritin]. Moreover, GDF15 was inversely related to hemoglobin, suggesting a potential link to iron homeostasis. Furthermore, GDF15 showed good classification capacity and improved the accuracy of a logistic regression model for ischemic HF classification in patients with ID. Overall, the findings of this study propose serum GDF15 levels as a potential tool for the classification of HF patients with ID according to the ischemic etiology.

Keywords:  GDF15; heart failure; iron deficiency; ischemic etiology

DOI:  https://doi.org/10.3390/biom15091234
FEBS J. 2025 Sep 25.

Fractalkine is a key player in skeletal muscle metabolism and pathophysiology.

Gourabamani Swalsingh, Punyadhara Pani, Sakthivel Sadayappan, Naresh Chandra Bal.

  Fractalkine (CX3CL1) is increasingly recognised for its role in regulating the metabolism of various tissues, including skeletal muscle. The circulating level of CX3CL1 is influenced by multiple organs including the brain, adipose tissue and immune cells, with skeletal muscles emerging as a significant source. Growing evidence shows that CX3CL1 modulates muscle metabolism through autocrine and paracrine mechanisms as well as influencing properties (i.e. migration, secretion, cellular communication) of local immune cells. Within skeletal muscle, CX3CL1-signaling is involved in the regulation of fibre-type composition, mitochondrial remodeling, local inflammation, and regenerative capacity. These actions affect muscle plasticity and adaptability in both resting and active states. CX3CL1 also facilitates substrate uptake, particularly glucose and lipids, by interacting synergistically with insulin-signaling pathways, especially during metabolic stress or exercise. Furthermore, CX3CL1 contributes to the coordination of skeletal muscle function with other key metabolic organs such as adipose tissue, liver and brain. Notably, CX3CL1 appears to play a role in the pathogenesis of several chronic diseases, including type 2 diabetes (T2D), obesity, cardiovascular disease (CVD), insulin resistance (IR) and arthritis. These findings underscore the relevance of CX3CL1 in both health and disease. Here, we critically assess recent advances in CX3CL1 research, including its mechanism of action, and explore its potential implications in physiological and pathological scenarios.

Keywords:  CX3CL1; exercise insulin; mitochondria metabolism; skeletal muscle; substrate utilisation

DOI:  https://doi.org/10.1111/febs.70267