bims-stacyt 2025-07-27 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–07–27
thirteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Unraveling the role of STAT3 in Cancer Cachexia: pathogenic mechanisms and therapeutic opportunities.
Activation of the integrated stress response and loss of cFLIPL under glutamine limitation induce IL-8 gene expression and secretion in glutamine-dependent tumor cells.
PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.
Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.
Assessment of the primary cancer cell secretome using amino acid-analog labeling.
Endoplasmic Reticulum Stress Amplifies Cytokine Responses in Astrocytes via a PERK/eIF2α/JAK1 Signaling Axis.
Epigenetic upregulation of FGF2 promotes glioblastoma progression by enhancing the Warburg effect.
Oncostatin M Drives Th2 Polarized Allergic Airway Inflammation Through Fibroblast Reprogramming and Endoplasmic Reticulum Stress.
Isolation of tumor interstitial fluid for metabolic determinations.
mTORC1 senses glutamine and other amino acids through GCN2.
Extracellular Vesicles as Multiorgan Crosstalk Mediators in Cardiovascular Diseases: Emerging Biomarkers and Therapeutic Targets.
Early methionine availability attenuates T cell exhaustion.
Inhibition of Glycolysis Modulates Retinal Endothelial Cell Function and Pathological Neovascularization.

Front Endocrinol (Lausanne). 2025 ;16 1608612

Unraveling the role of STAT3 in Cancer Cachexia: pathogenic mechanisms and therapeutic opportunities.

Xinyi Lv, Shengguang Ding.

  Cancer cachexia is a complex, multifactorial syndrome characterized by severe weight loss, muscle wasting, and systemic inflammation, significantly contributing to cancer-related morbidity and mortality. Signal transducer and activator of transcription 3 (STAT3) has emerged as a central mediator in the pathogenesis of this multifactorial condition. STAT3 regulates a broad range of cellular processes including inflammation, proteolysis, and mitochondrial dysfunction across multiple tissues, particularly skeletal muscle and adipose tissue. Persistent activation of STAT3 in response to tumor-derived and host-derived cytokines drives catabolic signaling cascades, disrupts anabolic pathways, and impairs energy homeostasis. Recent studies have illuminated the cross-talk between STAT3 and other signaling pathways that exacerbate cachexia-related metabolic imbalances. These findings position STAT3 not only as a critical mediator of cachexia progression but also as a promising therapeutic target. Pharmacological inhibition of STAT3 signaling has demonstrated efficacy in preclinical models, offering potential avenues for clinical intervention. This review provides a comprehensive overview of the molecular mechanisms by which STAT3 contributes to cancer cachexia and discusses emerging therapeutic strategies aimed at modulating STAT3 activity to mitigate the progression of this debilitating syndrome.

Keywords:  STAT3; cancer cachexia; muscle wasting; pathogenic mechanisms; systemic inflammation; therapeutic strategies

DOI:  https://doi.org/10.3389/fendo.2025.1608612
Cell Death Discov. 2025 Jul 19. 11(1): 332

Activation of the integrated stress response and loss of cFLIPL under glutamine limitation induce IL-8 gene expression and secretion in glutamine-dependent tumor cells.

Rocío Mora-Molina, F Javier Fernández-Farrán, Abelardo López-Rivas, Carmen Palacios.

Growing evidence suggests that the proapoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) signaling pathway can also trigger the production of inflammatory cytokines, thereby promoting tumor progression. We recently reported that glutamine depletion impacts the survival of glutamine-dependent tumor cells by activating the TRAIL-R2/DR5-mediated apoptotic machinery. However, it remains unclear whether glutamine limitation activates a TRAIL-R2/DR5-regulated inflammatory response. In this study, we demonstrate that glutamine starvation activates two parallel signaling pathways, leading to the gene expression and secretion of the pro-angiogenic and pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells. Our findings reveal that the amino acid-sensing general control nonderepressible-2 kinase (GCN2)/activating transcription factor 4 (ATF4) signaling axis contributes to the upregulation of IL-8 gene expression in glutamine-deprived tumor cells. Furthermore, our results indicate that the loss of the long isoform of cellular FLICE-inhibitory protein (cFLIPL), which occurs as result of the metabolic stress induced by glutamine limitation, promotes TRAIL-independent activation of the NF-kB pathway via TRAIL-R2/DR5, a key mechanism driving the observed IL-8 upregulation under starvation conditions. Given the severe depletion of glutamine observed in growing tumors, our data suggest that IL-8 secretion, induced by this metabolic stress, may play a significant role in activating inflammatory and angiogenic responses, thereby counteracting apoptosis and ultimately promoting tumor progression.

DOI: https://doi.org/10.1038/s41420-025-02625-3
J Biol Chem. 2025 Jul 21. pii: S0021-9258(25)02354-3. [Epub ahead of print] 110504

PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.

Shixin Zhou, Zihan Zhou, Si Chen, Ming Wang, Likun Wang.

  The unfolded protein response (UPR) initiated under endoplasmic reticulum (ER) stress can not only maintain the ER homeostasis, but also modulate the secretion of proteins and lipids that transmit ER stress signals among cells. Exosomes are multivesicular body (MVB)-derived extracellular vesicles, constituting the unconventional protein secretion pathway. Whether and how the secretion of exosomes is regulated by the UPR remains largely unknown. Here, we reported that ER stress induces exosome secretion in an UPR-dependent way. Activation of PERK and IRE1α, two of the UPR branches, represses the acidification and catabolic activity of lysosomes. This blocked MVB-lysosome fusion, re-directing MVBs from lysosomal degradation to plasma membrane fusion, resulting in exosome release. Calcium-mediated activation of PERK, in the absence of ER stress, is sufficient to suppress lysosomal degradation and augment exosome secretion, partly through its downstream factor ATF4. Our study revealed a function of PERK and IRE1α in modulating lysosome activity and dictating the fate of MVBs, facilitating cell-cell communication via exosomes.

Keywords:  IRE1α; PERK; extracellular vesicle; lysosome; unfolded protein response

DOI:  https://doi.org/10.1016/j.jbc.2025.110504
Cell. 2025 Jul 18. pii: S0092-8674(25)00741-X. [Epub ahead of print]

Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.

Doris Kaltenecker, Søren Fisker Schmidt, Peter Weber, Anne Loft, Pauline Morigny, Juliano Machado, Julia Geppert, Kerstin Beate Saul, Pia Benedikt, Claudia-Eveline Molocea, Rachel Scott, Kerstin Haase, Marc E Martignoni, Ana Jimena Alfaro, Kan Kau Chow, Estefania Simoes, José Pinhata Otoch, Joanna D C C Lima, Charles Swanton, Nadine Spielmann, Martin Hrabé de Angelis, Markus Elsner, Ali Ertürk, Kenneth A Dyar, Maria Rohm, Olga Prokopchuk, Mariam Jamal-Hanjani, Marilia Seelaender, Johannes Backs, Stephan Herzig, Mauricio Berriel Diaz.

  In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBα in cachexia ameliorated peripheral tissue wasting. This improvement was associated with decreased levels of specific cachexia-controlled hepatocyte-secreted factors. These hepatokines promoted catabolism in multiple cell types and were elevated in cachectic cancer patients. Our findings reveal a mechanism by which the liver contributes to peripheral tissue wasting in cancer cachexia, offering perspectives for future therapeutic interventions.

Keywords:  INTACT; REV-ERB; adipose tissue wasting; cachexia; circadian clock; hepatic reprogramming; liver-secreted factors; muscle atrophy

DOI:  https://doi.org/10.1016/j.cell.2025.06.039
Methods Cell Biol. 2025 ;pii: S0091-679X(24)00239-5. [Epub ahead of print]196 43-65

Assessment of the primary cancer cell secretome using amino acid-analog labeling.

Annemieke C Bouwman, Antoinette van Weverwijk, Onno B Bleijerveld, Liesbeth Hoekman, Bob J Ignacio, Kimberly M Bonger, Karin E de Visser.

  It is well established that reciprocal communication between cancer cells and other cells in the tumor microenvironment plays a crucial role in cancer progression and therapy response. There are multiple ways by which cells communicate, including direct cell-cell contact and the secretion of soluble mediators. The secretome of cancer cells contains valuable information to disentangle the complex conversation that is happening between cancer cells and neighboring or distant cells such as immune cells, fibroblasts and endothelial cells. Here, we provide a workflow of mapping the cancer cell secretome in an unbiased way using amino acid-analog labeling in combination with mass spectrometry. The generation of single cells from fresh tumors, isolation of primary cancer cells from a complex multi-cellular pool, and the detection of newly synthesized proteins that are secreted into the medium is described in detailed protocols. Using this experimental pipeline the secretome of cancer cells across different tumors can be determined, paving the way to unravel cell-cell communication networks in the tumor microenvironment, which may uncover novel therapeutic targets.

Keywords:  Amino acid-labeling; Cancer cell secretome; Cancer-immunity crosstalk; Cell-cell interaction; Mass spectometry; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.mcb.2024.11.002
Glia. 2025 Jul 20.

Endoplasmic Reticulum Stress Amplifies Cytokine Responses in Astrocytes via a PERK/eIF2α/JAK1 Signaling Axis.

Anirudhya Lahiri, Savannah G Sims, Jessica A Herstine, Alicia Meyer, Micah J Marshall, Ishrat Jahan, Subhodip Adhicary, Allison M Bradbury, Gordon P Meares.

  Aberrant activation of multiple cellular processes and signaling pathways is a hallmark of many neurological disorders. Understanding how these processes interact is crucial for elucidating the neuropathogenesis of these diseases. Among these, endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and neuroinflammation are frequently implicated. Previously, we demonstrated that ER stress synergizes with tumor necrosis factor (TNF)-α to amplify interleukin (IL)-6 and C-C motif chemokine ligand (CCL)20 production in astrocytes through a Janus kinase 1 (JAK1)-dependent mechanism. Here, we expand on this finding by defining the scope and underlying mechanisms of this phenomenon. We show that ER stress and TNF-α cooperatively enhance inflammatory gene expression in astrocytes via a signaling axis that requires both protein kinase R (PKR)-like ER kinase (PERK) and JAK1. PERK-mediated phosphorylation of eukaryotic translation initiation factor (eIF)2α suppresses protein translation, delaying the expression of negative regulators such as NF-κB inhibitor (IκB)α and suppressor of cytokine signaling (SOCS)3 following TNF-α or oncostatin M (OSM) stimulation, respectively. Pharmacological reversal of p-eIF2α-dependent translational suppression using the small molecule integrated stress response inhibitor (ISRIB) restored IκBα and SOCS3 expression and attenuated the ER stress-induced enhancement of TNF-α- or OSM-driven inflammatory responses. Notably, astrocytes harboring a vanishing white matter-associated EIF2B5 mutation revealed that translational attenuation alone is insufficient to amplify cytokine-induced gene expression. Together, these findings identify a PERK/eIF2α/JAK1 signaling axis that sensitizes astrocytes to inflammatory cytokines, providing new mechanistic insights into the interactions between ER stress and neuroinflammation.

Keywords:  IL‐6; JAK/STAT; glia; integrated stress response; neuroinflammation; unfolded protein response

DOI:  https://doi.org/10.1002/glia.70067
Cell Signal. 2025 Jul 18. pii: S0898-6568(25)00426-7. [Epub ahead of print]135 112011

Epigenetic upregulation of FGF2 promotes glioblastoma progression by enhancing the Warburg effect.

Yefeng Shi, Yang Zhang, Le Xu, Changwei Luo, Shun Xi, Xinyu Xu, Jianquan Liu, Haoyue Xu, Baole Zhang.

  Glioblastoma (GBM), the most common primary intracranial malignancy, remains poorly understood in terms of its underlying etiology. Although fibroblast growth factor 2 (FGF2) is highly expressed in GBM, its epigenetic regulation and functional contributions to disease progression are incompletely defined. Here, through integrated bioinformatics analysis, real-time PCR, and western blot, we demonstrate that FGF2 expression is significantly upregulated in GBM patient-derived tissues and cells. Functional assays revealed that silencing FGF2 markedly suppressed GBM cell proliferation and migration in vitro. Mechanistically, we identified cyclic AMP response element-binding protein 1 (CREB1) as a critical transcription factor regulating FGF2 transcription through binding to cAMP response elements (CREs) within the FGF2 gene's silencer I and core promoter regions. Intriguingly, these CREs exerted opposing regulatory effects: hypermethylation of the silencer I and hypomethylation of the core promoter favored preferential CREB1 binding to the core promoter in GBM cells. CREB1 recruitment of histone acetyltransferase CBP further promoted histone H3K27 acetylation and enhanced chromatin accessibility at the FGF2 core promoter, thereby driving transcriptional activation. Additionally, FGF2 has been shown to significantly enhance glycolysis and lactate production in GBM cells, fueling malignant growth. Collectively, our findings highlight the CREB1/FGF2/lactate axis as a promising therapeutic target for GBM treatment.

Keywords:  CBP; CREB1; FGF2; Glioblastoma; Warburg effect

DOI:  https://doi.org/10.1016/j.cellsig.2025.112011
Int J Nanomedicine. 2025 ;20 9019-9030

Oncostatin M Drives Th2 Polarized Allergic Airway Inflammation Through Fibroblast Reprogramming and Endoplasmic Reticulum Stress.

Huanping Zhang, Xiaoxue Chen, Le Liu, Haoyue Zheng, Xing Yang, Kai Yin, Qi Yao, Lei Li, Pingchang Yang.

   Background: Allergic airway inflammation, characterized by Th2 cytokine production and eosinophilic infiltration, is a hallmark of asthma. The airway epithelium plays a pivotal role in orchestrating allergic responses by releasing cytokines such as oncostatin M (OSM). This study investigates the role of OSM in dust mite extract (DME)-induced allergic airway inflammation and identifies a novel mechanism by which OSM drives Th2-polarized inflammation.
Methods: A murine model of DME-induced airway inflammation was established. Mice were treated with CelEd, a nanoparticle carrying fibroblast-targeting device and ATF4 siRNA.
Results: We observed that DME exposure significantly upregulates OSM expression in airway epithelial cells, both at the mRNA and protein levels. This finding was corroborated in human bronchial epithelial cell lines, where DME exposure induced dose-dependent OSM secretion. Intranasal administration of OSM in naïve mice phenocopied the hallmark features of allergic inflammation, including eosinophilic infiltration and elevated Th2 cytokines, highlighting OSM's sufficiency to drive allergic responses. Mechanistically, we discovered that OSM promotes IL-4 production through fibroblast reprogramming, involving endoplasmic reticulum stress (ERS) activation. OSM signaling in fibroblasts led to ERS and subsequent activation of the PERK-eIF2α-ATF4 pathway, which drives IL-4 transcription via the ATF4/Mef2d/GATA3 axis. Importantly, targeting this pathway through fibroblast-specific ATF4 knockdown significantly alleviated allergic pathology, including airway eosinophilia, Th2 cytokine production, and airway hyperresponsiveness.
Conclusion: These findings underscore the critical role of OSM in allergic airway inflammation and identify the OSM-ERS-IL-4 axis as a potential therapeutic target for asthma and other allergic diseases.

Keywords:  ERS; IL-4; OSM; Oncostatin M; airway fibroblasts; allergic airway inflammation; endoplasmic reticulum stress

DOI:  https://doi.org/10.2147/IJN.S535265
Methods Cell Biol. 2025 ;pii: S0091-679X(24)00241-3. [Epub ahead of print]196 177-192

Isolation of tumor interstitial fluid for metabolic determinations.

Ainhoa Ruiz-Iglesias, Ángel García-Aldea, Elena Nonnast, Rosa M Peregil, Santos Mañes.

  Neoplastic cells are characterized by alterations in metabolic pathways, typically leading to an aberrant use of glycolysis even under aerobic conditions - a phenomenon known as the Warburg effect. One consequence of this metabolic shift is the production of lactate, an oncometabolite often found at elevated levels in tumors. Lactate not only fuels the growth of cancer cells but also promotes angiogenesis, immune escape, and metastasis, thereby contributing to tumor progression and resistance to therapy. This highlights the importance of lactate in cancer metabolism and underscores the need for methods to measure it. In this study, we describe various centrifugation and elution protocols to isolate interstitial fluid and measure lactate in experimental tumors. These tumors were generated in immunocompetent mice using the MC38 colon cancer cell line. We propose that, with minor modifications, the methods here described could be successfully adapted for use with tumors originating from other human or murine cell lines. Furthermore, these methods could potentially enable the detection of other oncometabolites in the tumor microenvironment, which could have significant implications for both basic research and therapeutic strategies.

Keywords:  Extracellular space; Glycolysis; Lactate; Oncometabolites; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.mcb.2024.11.004
EMBO J. 2025 Jul 21.

mTORC1 senses glutamine and other amino acids through GCN2.

Gianluca Figlia, Sandra Müller, Fabiola Garcia-Cortizo, Marilena Neff, Glynis Klinke, Gernot Poschet, Aurelio A Teleman.

  mTORC1 promotes cell growth when nutrients such as amino acids are available. While dedicated sensors relaying availability of leucine, arginine and methionine to mTORC1 have been identified, it is still unclear how mTORC1 senses glutamine, one of its most potent inducers. Here, we find that glutamine is entirely sensed through the protein kinase GCN2, whose initial activation is not triggered by depletion of glutamine itself, but by the concomitant depletion of asparagine. In turn, GCN2 leads to a succession of events that additively inhibit mTORC1: within 1 h, GCN2 inhibits mTORC1 through the Rag GTPases, independently of its function as an eIF2α kinase. Later, GCN2-mediated induction of ATF4 upregulates Ddit4 followed by Sestrin2, which together cause additional mTORC1 inhibition. Additionally, we find that depletion of virtually any other amino acid also inhibits mTORC1 through GCN2. GCN2 and the dedicated amino acid sensors thus represent two independent systems that enable mTORC1 to perceive a wide spectrum of amino acids.

Keywords:  Amino Acid Sensors; Asparagine; GCN2; Glutamine; mTORC1

DOI:  https://doi.org/10.1038/s44318-025-00505-1
Eur J Pharmacol. 2025 Jul 18. pii: S0014-2999(25)00730-7. [Epub ahead of print] 177976

Extracellular Vesicles as Multiorgan Crosstalk Mediators in Cardiovascular Diseases: Emerging Biomarkers and Therapeutic Targets.

Fanji Meng, Lixia Zhou, Baokai Zhang, Yayue Wang, Yunpeng Bai, Ying Han, Liliang Wang, Jing Xu.

  Under normal physiological conditions, the body operates through the intricate coordination of multiple organs, with the heart serving as a central energy engine that communicates with other organs. Conversely, both physiological and pathological states can influence cardiac activity via neural and humoral regulation. Extracellular vesicles (EVs) are nanoscale, lipid-bound particles secreted by nearly all cell types. These vesicles are rich in proteins, lipids, sugars, and genetic material, facilitating intercellular communication. EVs achieve this by fusing with or being endocytosed by recipient cells, thereby transferring bioactive molecules. While considerable research has explored the role of EVs in inter-organ communication, the specific mechanisms by which EVs link the cardiovascular system to other organs remain insufficiently understood. This review aims to elucidate the critical function of extracellular vesicles in bridging the cardiovascular system and other organs, with particular emphasis on intracardiac communication and major inter-organ communication pathways, providing a comprehensive analysis of recent findings in this evolving area of study.

Keywords:  Cardiac inter-organ communication; Exosomes; Extracellular vesicles

DOI:  https://doi.org/10.1016/j.ejphar.2025.177976
Nat Immunol. 2025 Jul 23.

Early methionine availability attenuates T cell exhaustion.

Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.

T cell receptor (TCR) activation is regulated in many ways, including niche-specific nutrient availability. Here we investigated how methionine (Met) availability and TCR signaling interplay during the earliest events of T cell activation affect subsequent cell fate. Limiting Met during the initial 30 min of TCR engagement increased Ca2+ influx, NFAT1 (encoded by Nfatc2) activation and promoter occupancy, leading to T cell exhaustion. We identified changes in the protein arginine methylome during initial TCR engagement and identified an arginine methylation of the Ca2+-activated potassium transporter KCa3.1, which regulates Ca2+-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering T cells dysfunctional in mouse tumor and infection models. Furthermore, acute, early Met supplementation reduced nuclear NFAT1 in tumor-infiltrating T cells and augmented antitumor activity. These findings identify a metabolic event early after T cell activation that affects cell fate.

DOI: https://doi.org/10.1038/s41590-025-02223-6
Exp Eye Res. 2025 Jul 21. pii: S0014-4835(25)00306-9. [Epub ahead of print] 110535

Inhibition of Glycolysis Modulates Retinal Endothelial Cell Function and Pathological Neovascularization.

David Hughes, Pietro M Bertelli, Edoardo Pedrini, Lynsey-Dawn Allen, Cristina Branco, Tim M Curtis, Reinhold J Medina, Alan W Stitt, Judith Lechner.

  In many retinopathies, hypoxia stimulates pathogenic neovascularization. The precise impact of hypoxia and how it may drive a switch in retinal microvascular endothelial cell metabolism during active angiogenesis remains ill-defined. This study has sought to understand dynamic shifts in the metabolic profile of retinal microvascular endothelial cells exposed to hypoxia and during ischemia-induced neovascularization. The impact of manipulating glycolytic metabolism by intravitreal injection of the glycolytic inhibitor 3-(3-Pyridinyl)-1-(4pyridinyl)-2-propen-1-one) (3PO) on pre-retinal neovascularization was investigated using the oxygen-induced retinopathy (OIR) model. Metabolic pathways generating adenosine triphosphate (ATP) in human retinal microvascular endothelial cells (HRMECs) was evaluated using qPCR and the Seahorse XFe96 analyzer under normal culture conditions and hypoxia +/- 3PO. The role of glycolysis in HRMEC angiogenesis related processes such as tubulogenesis, proliferation and migration were assessed when glycolysis was blocked by 3PO. Our study showed that intravitreal injection of 3PO in the OIR model inhibited pre-retinal neovascularization compared to vehicle injected controls (P<0.0001). While hypoxia increased glycolysis in HRMECs, treatment with 3PO reduced their glycolytic activity under normoxia and hypoxia culture conditions. Treatment with 3PO, reduced glycolytic mRNA expression of GLUT1, HK1, PFKFB3, ENO2 and VEGFA. Finally, glycolytic inhibition reduced tubulogenesis (p < 0.05), migratory capacity (p < 0.001) and proliferation (p < 0.01) of HRMECs in vitro. This data suggests that retinal angiogenesis can be modulated by manipulating the glycolytic pathway using 3PO in vivo and that 3PO treatment in vitro can diminish the angiogenic potential of HRMECs.

Keywords:  3PO; Angiogenesis; Glycolytic inhibitor; Human retinal microvascular endothelial cells (HRMECS); Oxygen induced retinopathy (OIR); Retinal neovascularization; glycolysis

DOI:  https://doi.org/10.1016/j.exer.2025.110535