bims-stacyt 2026-07-05 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–07–05
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.
The role of ATF4 in neurons under mitochondrial stress.
Resveratrol Attenuates Obesity by Inducing GDF15 Expression via the p38-ATF3 Signaling Pathway.
Squalene Alleviates Cancer Cachexia-Induced Muscle Atrophy and Adipose Tissue Wasting in CT26 Tumor-Bearing Mice.
Allosteric disordering of eIF2B regulates the integrated stress response.
Neural-tumor crosstalk in driving tumor metabolic reprogramming.
HK2 knockdown is associated with context-dependent inflammatory and angiogenesis-related transcriptional programmes in glioblastoma cells.
Immune-tumor cell ligand-receptor axes driving metabolic reprogramming and therapeutic resistance in cancer.

Science. 2026 Jul 02. 393(6806): 90-97

A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.

Michael Cross, Stefan Kotschi, Warren Wu, Fedra Luciano-Mateo, Young-Yon Kwon, Ezequiel Dantas, Taha Niazi, Shijia Chen, Ali Rashidfarrokhi, Ray Pillai, Jack Sanford, Jeshua Kim, Juliya Hsiang, Begona Gamallo-Lana, Adam C Mar, Yuan Hao, Sahith Rajalingam, Annie Huang, Jackie Shan, Habon A Issa, Maria Gomez, Alice R Wang, Xiang Zhao, Tobias Janowitz, Eileen White, Yin Liu, Kwok-Kin Wong, Leopoldo N Segal, Sheng Hui, Marcus D Goncalves, Robert C Froemke, Thales Papagiannakopoulos.

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.

DOI: https://doi.org/10.1126/science.adz4196
NAR Genom Bioinform. 2026 Sep;8(3): lqag069

The role of ATF4 in neurons under mitochondrial stress.

Maria Bilen, Yubing Liu, Imane Chakroun, Mohamed Ariff Iqbal, Bensun C Fong, Jingwei Chen, Smitha Paul, Alexandre Blais, Ruth S Slack.

Mitochondrial dysfunction and fragmentation are observed in various circumstances, such as neurodegeneration and aging. Studies have shown that altered mitochondrial function activates the integrated stress response (ISR), with ATF4 serving as a major mediator of adaptation to stress. Presently, little is known about the role of ATF4 in neurons under mitochondrial stress. Using primary cortical neurons, we demonstrate that inhibiting ATF4 under OPA1-mediated mitochondrial stress accelerates the impairment of neuronal differentiation, as evidenced by smaller dendrites and lower dendritic spine density. To better understand the role of ATF4 in this context, we investigated the global binding sites of ATF4 using chromatin immunoprecipitation sequencing (ChIP-seq) and examined the chromatin accessibility changes that occur following the loss of ATF4 in neurons under conditions of mitochondrial stress. We found that ATF4 binds to a wide range of targets and alters the chromatin accessibility of genes involved in metabolism, neuronal fate, and neuron maturation. The downstream targets of ATF4 identified in this study can reveal novel and direct targets of ATF4 in neuronal survival and maturation. These adaptations are the hallmarks of stress response in mitochondrial dysfunction-mediated neurodegeneration.

DOI: https://doi.org/10.1093/nargab/lqag069
Food Sci Nutr. 2026 Jul;14(7): e72052

Resveratrol Attenuates Obesity by Inducing GDF15 Expression via the p38-ATF3 Signaling Pathway.

Liufeng Mao, Yunliang Hou, Weifang Liu, Jianbin Chen, Wanli Hu, Wengong Jiang, Tao Nie.

  Resveratrol, a natural polyphenol, has been widely studied for its potential health benefits in obesity treatment, but its molecular mechanism remains elusive. This study investigates the molecular mechanisms by which resveratrol promotes the expression and secretion of Growth Differentiation Factor 15 (GDF15), a key regulator of energy homeostasis. Using both murine embryonic fibroblasts (MEFs) and human HepG2 cells, resveratrol dose-dependently upregulates Gdf15 mRNA and protein expression, as well as increases GDF15 secretion. Transcriptome analysis and subsequent validation experiments revealed that Activating Transcription Factor 3 (ATF3) mediates the effect of resveratrol on GDF15 expression. Additionally, resveratrol-treated mice exhibited resistance to high-fat diet-induced obesity and increased plasma GDF15 levels. In vivo studies in mice further confirmed that resveratrol treatment elevates GDF15 levels in liver, kidney, and colon tissues, and enhances downstream ERK signaling in the brain. Collectively, these findings suggest that GDF15 plays a critical role in mediating the anti-obesity effects of resveratrol.

Keywords:  ATF3; ERK signaling; GDF15; obesity; resveratrol

DOI:  https://doi.org/10.1002/fsn3.72052
J Nutr Biochem. 2026 Jun 29. pii: S0955-2863(26)00199-3. [Epub ahead of print] 110457

Squalene Alleviates Cancer Cachexia-Induced Muscle Atrophy and Adipose Tissue Wasting in CT26 Tumor-Bearing Mice.

Yeeun Kim, Junhui Kang, Sungmin Han, Junhee Lee, Hyunju Kang, Jae-Kwan Hwang, Mi-Bo Kim.

  Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive loss of body weight, skeletal muscle, and adipose tissue, primarily driven by chronic inflammation and systemic energy imbalance. Squalene (SQ), a naturally occurring triterpenoid abundant in shark liver oil, exhibits potent antioxidant and anti-inflammatory properties. In this study, we investigated the protective effects of SQ against cancer-induced skeletal muscle and adipose tissue wasting in CT26 tumor-bearing mice. Seven days after CT26 colon carcinoma implantation, BALB/c mice were orally administered SQ (150 or 300 mg/kg/day) or saline for 17 days. SQ supplementation significantly attenuated tumor-induced body weight loss and anorexia, along with a reduction in tumor weight in cachectic mice. Furthermore, SQ prevented the loss of muscle mass and fiber cross-sectional area, accompanied by enhanced grip strength. In the gastrocnemius muscle, SQ inhibited nuclear factor kappa B activation, thereby suppressing the expression of inflammatory cytokines while enhancing antioxidant enzyme expression. These effects collectively reduced protein degradation through the forkhead box O3a pathway and promoted protein synthesis and myogenesis via reactivation of phosphatidylinositol 3-kinase/Akt signaling. Molecular docking analysis further suggested that SQ potentially modulates PI3K activity by favorably occupying its regulatory pocket. In adipose tissue, SQ alleviated fat wasting by suppressing AMPK phosphorylation, leading to reduced lipolysis and fat browning and enhanced adipogenic/lipogenic gene expression. Overall, these findings demonstrate that SQ mitigates cancer-induced muscle and adipose tissue wasting through modulation of catabolic signaling pathways, highlighting its potential as a nutritional intervention for cancer cachexia.

Keywords:  adipose tissue wasting; cancer cachexia; muscle atrophy; squalene

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110457
Nat Chem Biol. 2026 Jun 29.

Allosteric disordering of eIF2B regulates the integrated stress response.

Udit Dalwadi, Advait Subramanian, Aniliese Deal, Julia E Conrad, Tamara Nadjsombati, Meera Venkatesh, Morgane Boone, Pascal F Egea, Lingjie He, Nimit Jain, D John Lee, Yuwei Liu, Lucas C Reineke, Kazuki Saito, Nathaniel Talledge, Hannah Toutkoushian, Maxence Le Vasseur, Francesca Zappa, Raoul J de Groot, Diego Acosta-Alvear, Christopher P Arthur, Jodi Nunnari, Susan Marqusee, Rosalie E Lawrence, Mauro Costa-Mattioli, James J Crawford, Frank J M van Kuppeveld, Tristan I Croll, Peter Walter, Adam Frost.

The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.

DOI: https://doi.org/10.1038/s41589-026-02256-4
Biochim Biophys Acta Rev Cancer. 2026 Jun 28. pii: S0304-419X(26)00116-2. [Epub ahead of print]1881(4): 189644

Neural-tumor crosstalk in driving tumor metabolic reprogramming.

Xia Xiao, Congcong Zhang, Jiahao Chen, Jiayi Zhang, Hanyu Li, Weiming Yu, Xianlei Cai.

  Neural-tumor interactions have emerged as critical drivers of metabolic reprogramming in cancer. This review systematically examines how neural signaling reshapes tumor metabolism through a conceptual framework that classifies neural-tumor crosstalk into three principal modes: direct physical contacts, paracrine signaling, and indirect mediation via immune and glial cells. Key neurotransmitters (norepinephrine, acetylcholine, glutamate) and neurotrophic factors (NGF, BDNF) engage specific receptors on tumor cells, activating downstream signaling cascades that regulate glycolysis, lipid synthesis, and amino acid metabolism. Central to this axis is lactate, which not only fuels tumor growth but also drives histone lactylation, an epigenetic modification that links metabolic flux to sustained transcriptional reprogramming. Beyond the lactate-centered model, emerging mechanisms-including mitochondrial transfer via tunneling nanotubes, extracellular vesicle-mediated metabolic hijacking, and direct nutrient supply by neurons-reveal the remarkable diversity of neural-driven metabolic regulation. The neuro-immune-metabolic circuit adds another layer of complexity, whereby neural signals reprogram immune cell metabolism to create an immunosuppressive microenvironment. This review further evaluates therapeutic strategies targeting the neural-metabolic axis, from repurposed β-blockers to Trk inhibitors and metabolic interventions. By integrating these multifaceted interactions into a unified framework, we highlight future research directions and therapeutic opportunities that may yield novel treatments targeting the neural-metabolic interface in cancer.

Keywords:  Lactate; Metabolic reprogramming; Neural-tumor crosstalk; Neuro-immune-metabolic circuit; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189644
Front Immunol. 2026 ;17 1842240

HK2 knockdown is associated with context-dependent inflammatory and angiogenesis-related transcriptional programmes in glioblastoma cells.

Christopher Edwards, Taylor Richards, Hafid Omar Al-Hassi, Surya Prakash Shivakumar, Benjamin Small, Kate Butcher, Tracy Warr, Mark Morris, Timothy Dawson, Michael D Jenkinson, Katherine Karakoula.

   Introduction: Deregulation of cellular metabolism is a hallmark of cancer, in which tumour cells upregulate glycolysis and preferentially ferment glucose to lactate in the 'Warburg effect'. Tumour-specific upregulation of hexokinase 2 (HK2), which catalyses the first rate-limiting step of glycolysis, is a key driver of this phenotype and represents a promising therapeutic target in glioblastoma. Here, we sought to identify HK2-associated tumour processes that could serve as therapeutic co-targets by profiling the transcriptomic consequences of HK2 knockdown (HK2KD) in model established glioblastoma cell lines and patient-derived short-term cell cultures.
Methods: Glioblastoma cell lines and patient-derived short-term cell cultures were subjected to HK2KD using HK2-targeted siRNA. Glycolytic activity was assessed using the Seahorse Glycolytic Stress Test, and transcriptomic changes were analysed by RNA sequencing.
Results: HK2KD was associated with reduced glycolytic activity in high-HK2-expressing models as well as extensive transcriptional remodelling. Integrative analysis using RNA sequencing, gene ontology and pathway enrichment, protein-protein interaction networks, and transcriptome-based perturbation matching indicated coordinated modulation of inflammatory, immune-associated and angiogenesis-linked gene programmes, including cytokine, chemokine and pro-angiogenic signalling axes. Notably, inflammatory pathway responses diverged markedly between independent glioblastoma models, representing a central finding of this study and highlighting context-dependent immunometabolic transcriptional changes following HK2KD.
Discussion: These findings suggest that HK2KD is associated with transcriptional changes extending beyond glycolytic pathways, linking metabolic activity to immunological and angiogenic transcriptional networks in a model-dependent manner. Although functional effects on the tumour microenvironment were not directly assessed, this study provides a transcriptomic framework for understanding how HK2 targeting may be associated with changes in tumour-associated signalling pathways, with potential implications for stratified metabolic and combination therapeutic strategies in glioblastoma.

Keywords:  angiogenesis; chemokine; cytokine; glioblastoma; hexokinase; inflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1842240
Front Immunol. 2026 ;17 1864068

Immune-tumor cell ligand-receptor axes driving metabolic reprogramming and therapeutic resistance in cancer.

Hailin Zhu, Wang Yi, Yujie Wu, Rong Li, Boxuan Zhou.

  Therapeutic resistance remains a major barrier to durable cancer control and cannot be fully explained by tumor-intrinsic genetic and epigenetic alterations alone. Increasing evidence indicates that resistance emerges within a dynamic tumor microenvironment in which immune cells actively instruct tumor cell behavior through ligand-receptor (LR) signaling. These immune-tumor communication axes link inflammatory cues, checkpoint-associated signals, chemokine networks, and metabolite-derived messages to adaptive tumor phenotypes. In particular, these axes may contribute to metabolic reprogramming across glucose, lipid, amino acid, and redox pathways, thereby supporting tumor-cell proliferation, therapeutic stress tolerance, and immune evasion. Lactate-centered signaling, macrophage-derived cytokine and chemokine axes, and checkpoint-associated pathways such as PD-L1-related signaling have emerged as major regulators of this process. These LR-mediated circuits are increasingly associated with tumor metabolic remodeling, immune suppression, phenotypic plasticity, and reduced responsiveness to chemotherapy and immune checkpoint blockade. Recent advances in single-cell transcriptomics, spatial omics, multiplex imaging, metabolomics, and computational modeling are accelerating the mapping of these communication networks in situ and revealing clinically relevant resistance niches. In this review, we synthesize current evidence on how immune-tumor cell LR axes drive metabolic adaptation and therapeutic resistance across cancers, discuss the technologies enabling their dissection, and highlight their translational potential as biomarkers and therapeutic targets. Understanding these communication systems may provide new opportunities to disrupt resistant tumor ecosystems and improve the durability of cancer therapy.

Keywords:  drug resistance; immune checkpoint; immune–tumor communication; lactate signaling; ligand–receptor axis; metabolic reprogramming; spatial omics; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1864068