bims-stacyt 2026-03-15 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–03–15
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice.
A Unique Intercellular Feedforward Loop From HK1 to TGF-β1 Promotes the Progression of Hepatocellular Carcinoma.
Ageing promotes metastasis via activation of the integrated stress response.
Context-Dependent Role of GDF15: GDF15+ Tumor-Associated Macrophages Suppress OSCC Progression by Enhancing Phagocytosis.
Moderate Aerobic Training Causes Muscle Wasting in a DMBA-Induced Sarcoma Rat Model.
Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice.
Roles of the integrated stress response in regulation of inflammatory reactions.
Targeting the DSTYK-ULK1 axis rewires TNFR1 signaling to overcome treatment resistance in lung cancer.
Association between elevated expression of GDF15/GFRAL and sarcopenia risk.
Weight Loss During Obesity Provokes Asparaginase-Associated Liver Steatosis and Endoplasmic Reticulum Stress.

J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70237

Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice.

Cui Wang, Lin Gao, Rui Xue, Jia Su, Honghui Li, Wei Yang, Yan Tang, Zhihang Su, Shasha Min, Changyong Tang, Yuqi Zhu, Bo Mu, John R Speakman, Xina Xie, Zesong Li.

   BACKGROUND: Cancer cachexia is a multifactorial wasting syndrome marked by profound skeletal muscle loss. Tumours can release high levels of Activin A (ActA), which activates the ubiquitin-proteasome pathway (UPP) and drives muscle wasting. Systemic blockade of the ActA pathway is associated with inflammatory adverse effects, and tumour-restricted targeting alone often fails to reverse cachexia. We asked whether ActA produced by host (nontumour) organs contributes to circulating ActA and muscle wasting.
METHODS: We profiled ActA across tissues and in serum in Lewis lung carcinoma (LLC) cancer cachexia mice to generate an organ-wide expression map. Functional studies were then performed using adeno-associated-virus (AAV)-knockdown in the heart (cTnT/hTCF21 promoters) and kidney (CMV promoter), followed by cachexia induction. Body weight (BW), food intake, skeletal muscle mass, muscle function and muscle histomorphology were assessed. Mitochondrial ultrastructure and lipid metabolic pathways in muscle and adipose tissue were also examined.
RESULTS: LLC cachexia mice exhibited significant reductions in body weight (-6.0%, p < 0.05), food intake (-9.9%, p < 0.05), quadriceps mass (-15.3%, p < 0.05) and grip strength (-13.0%, p < 0.0001) compared with non-tumour-bearing (NTB) mice (n = 6-12/group). ActA expression was markedly increased in the host organs, particularly in the kidney (2.8-fold vs. NTB, p < 0.001) and heart (2.7-fold vs. NTB, p < 0.05) (n = 10/group). Compared with the sh-NC, organ-targeted ActA knockdown restored body weight (+6.1%, p < 0.05) and food intake (+8.4%, p < 0.05), increased quadriceps mass (+17.2%, p < 0.05) and grip strength (+10.7%, p < 0.01), reduced intramuscular fat infiltration and attenuated UPP signalling (n = 8-16/group). These effects were accompanied by increased expression of the mitochondrial fatty-acid oxidation regulator carnitine palmitoyltransferase 1B (CPT1B) (+42.3% of mRNA level; +30.9% of protein level; both p < 0.05) and CPT2 (+57.7% of mRNA level, p < 0.05), improved mitochondrial ultrastructure and partial restoration of adipose mass.
CONCLUSIONS: Simultaneous downregulation of Activin A in the kidney and heart attenuates skeletal muscle atrophy and intramuscular adipogenesis, improves muscle mass and function and mitigates adipose tissue mass loss in cancer cachexia mice. These findings identify heart- and kidney-derived Activin A as a key driver of cachexia, which acts through a combinatorial effect rather than an isolated contribution from either one alone, highlighting its potential as a therapeutic target.

Keywords:  Activin A; cancer cachexia; heart and kidney; intramuscular fat infiltration; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70237
J Extracell Vesicles. 2026 Mar;15(3): e70255

A Unique Intercellular Feedforward Loop From HK1 to TGF-β1 Promotes the Progression of Hepatocellular Carcinoma.

Qi-Tao Chen, Qiao-Ling Huang, De-Yi Feng, Wen-Xiu Zhao, Zhi-Yuan Zhang, Zhi-Hong Jiang, Ming-Zhi Han, Shui-Shun Chen, Yi Zhang, Qiao Wu, Hang-Zi Chen.

Hepatocellular carcinoma (HCC) typically emerges in a fibrotic premalignant liver milieu, and hepatic stellate cells (HSCs) represent the predominant cell subtype implicated in hepatic fibrosis. The crosstalk between HCC cells and HSCs has been demonstrated to affect HCC progression. Our prior research revealed that the activation of HSCs in hepatic fibrosis is accompanied with secretion of hexokinase 1 (HK1), an enzyme catalysing the initial step of glycolysis, through large extracellular vesicles (lEVs), which are selectively internalised by HCC cells to promote their glucose metabolism and tumour progression. In the present study, we found that the boosted glucose metabolism in HCC cells can reciprocally activate HSCs, thereby facilitating the formation of a pro-tumourigenic fibrotic microenvironment. Specifically, HSCs-transmitted lEV HK1 was identified as a key factor that markedly enhances the ability of HCC cells to activate HSCs. Mechanistically, HK1 accelerates the metabolic flux of hexosamine biosynthesis pathway, thereby promoting N-glycosylation of pro-transforming growth factor-β (TGF-β)1 and facilitating its secretion from HCC cells, which subsequently activates HSCs. This HCC cell-induced HSC activation is accompanied by increased secretion of lEV HK1 from HSCs, establishing a feedforward loop between HCC cells and HSCs. Furthermore, this intercellular communication was confirmed to exacerbate HCC progression in several mouse models, and disrupting this communication significantly inhibited HCC progression. Together, this study highlights that targeting the disruption of this feedforward loop may represent a promising and effective therapeutic strategy for HCC treatment.

DOI: https://doi.org/10.1002/jev2.70255
Nature. 2026 Mar 11.

Ageing promotes metastasis via activation of the integrated stress response.

Angana A H Patel, Jozefina J Dzanan, Kevin X Ali, Ella A Eklund, Samantha W Alvarez, Dorota Raj, Martin Dankis, Ilayda Altinönder, Maria Schwarz, Kristell Le Gal, Emre Bedel, Ahmed Ezat El Zowalaty, Emma Jonasson, Heba Albatrok, Nadia Gul, Jozef P Bossowski, Ray Pillai, Patrick Micke, Johan Botling, Levent M Akyürek, Davide Angeletti, Sama I Sayin, Anetta Härtlova, Thales Papagiannakopoulos, Roger Olofsson Bagge, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel, Volkan I Sayin.

Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.

DOI: https://doi.org/10.1038/s41586-026-10216-0
Adv Sci (Weinh). 2026 Mar 13. e18525

Context-Dependent Role of GDF15: GDF15+ Tumor-Associated Macrophages Suppress OSCC Progression by Enhancing Phagocytosis.

Xinyu Zhou, Zhihang Zhou, Houyu Ju, Chaoyang Guo, Fangxing Zhu, Yiyi Zhang, Xu Chen, Tongchao Zhao, Laiping Zhong, Jingzhou Hu.

  The growth differentiation factor 15 (GDF15) neutralizing antibody has shown to overcome resistance to immune checkpoint blockade (ICB) in various solid tumors. Though the therapeutic effect of GDF15 neutralizing antibody indicates a protumor role of secreted GDF15, the double-edged effect of GDF15 has remained a mystery for a long. Herein, we performed single-cell RNA-sequencing on oral squamous cell carcinoma (OSCC) samples before and after ICB-based therapy to explore the context-dependent functions of GDF15 across distinct cellular subsets. It revealed that GDF15+ macrophages were enriched in ICB-sensitive OSCCs after treatment and might participate in mediating tumor regression. Gdf15fl/flLyz2Cre mice illustrated that GDF15 deficiency in macrophages could accelerate tumor progression by suppressing the infiltration of CD8+ T cells. Mechanistically, macrophage-intrinsic GDF15 could enhance the abilities to phagocyte tumor cells and to cross-present antigens to CD8+ T cells. The functional enhancement of GDF15 was mediated through the upregulation of the NF-κB signaling pathway in macrophages. Collectively, the cellular source of GDF15 could determine its effect on tumor progression, with GDF15+ macrophages exerting an antitumor role in OSCC, whereas secreted GDF15 exerting a protumor role. The latter could be neutralized by the GDF15 antibody. These findings would advance a comprehensive understanding of the double-edged effect of GDF15.

Keywords:  growth differentiation factor 15; immune checkpoint blockade; oral squamous cell carcinoma; phagocytosis

DOI:  https://doi.org/10.1002/advs.202518525
Int J Mol Sci. 2026 Mar 04. pii: 2381. [Epub ahead of print]27(5):

Moderate Aerobic Training Causes Muscle Wasting in a DMBA-Induced Sarcoma Rat Model.

Rafael Ribeiro Correia, Allice Santos Cruz Veras, Maria Eduarda Almeida Tavares, Victor Rogério Garcia Batista, Sarah Santiloni Cury, Jakeline Santos Oliveira, Geysson Javier Fernandez, Brittany R Counts, Omnia U Gaafer, Sara Ota, Mateus Machado Frigo, Rebeca Vieira E Magalhães Rodrigues, Larissa Victorino Sampaio, Antonio Hernandes Chaves-Neto, Robson Francisco Carvalho, Teresa A Zimmers, Giovana Rampazzo Teixeira.

  Cancer cachexia, characterized by severe body weight loss, negatively affects patient quality of life and survival. Although moderate exercise benefits healthy and chronically ill individuals, and the effect of exercise in cachexia generally appears beneficial, conflicting results have been reported in cancer-associated cachexia. This study examined the effects of moderate aerobic exercise in a rat cancer model, focusing on molecular crosstalk among tumors, serum, and skeletal muscle. Male Sprague-Dawley rats were divided into Non-Cancer, Cancer, and Cancer + Exercise (Ex) groups. Cancer was induced with an intraperitoneal injection of 7,12-dimethylbenz[a]anthracene (DMBA), and the Cancer + Ex group completed an eight-week treadmill regimen. Tibialis anterior muscle, serum, and tumor tissues were analyzed by RNA sequencing. DMBA injection produced sarcoma-like tumors, reduced body weight, elevated inflammatory mediators, and activated muscle atrophy genes (Fbxo32). Exercise led to progressive intolerance, further weight loss, lower muscle mass, and larger tumors. Transcriptomic profiling revealed exacerbated cachexia signatures and suppressed energy metabolism genes in exercised cancer rats. Bioinformatic analysis of serum proteins and tissue transcriptomes identified enhanced chemokine-receptor signaling, including pro-tumorigenic (CXCL6_CXCR2) and pro-cachexia (CCL19_CXCR3, CCL5_CCR3, CXCL11_CXCR3) interactions. These findings suggest that in a pro-inflammatory cancer context, late-onset moderate exercise may worsen cachexia and stimulate tumor progression. Thus, exercise protocols should be cautiously tailored in cancer settings.

Keywords:  aerobic exercise; cancer cachexia; muscle wasting; transcriptomics; tumor

DOI:  https://doi.org/10.3390/ijms27052381
Cell Rep Med. 2026 Mar 09. pii: S2666-3791(26)00073-X. [Epub ahead of print] 102656

Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice.

Rafael Ferraz-Bannitz, Lei Pei, Hanna Wang, Berkcan Ozturk, Pilar Casanova Querol, Alessandra Gonçalves da Cruz, Tyler M Cook, Hamayle Saeed, Leila Osterwalder, Lindsay Poulos, Hany Saifeldin, Cameron Cummings, Maryam Farahmandsadr, Alessandra Amore, Amanda Sheehan, Donald C Simonson, Darleen A Sandoval, Mary-Elizabeth Patti.

  Post-bariatric hypoglycemia (PBH), characterized by excessive postprandial incretin and insulin secretion, is a common complication of bariatric surgery. Here, we investigate the relationship between PBH and growth differentiation factor 15 (GDF15) in individuals with PBH after Roux-en-Y gastric bypass (RYGB), post-RYGB individuals who remain asymptomatic (Asx), and individuals with overweight/obesity but without history of surgery (Ow/Ob). Fasting plasma GDF15 is higher in PBH vs. Ow/Ob and further increases postprandially, coinciding with hypoglycemia symptoms. During a hyperinsulinemic hypoglycemic clamp, GDF15 progressively increases in PBH and correlates with hypoglycemia survey symptoms, including weakness, difficulty concentrating, feeling cold, and tingling lips. In mice, insulin-induced hypoglycemia also results in elevated GDF15 levels, and exogenous recombinant GDF15 (rGDF15) reduces food intake in response to hypoglycemia. Our data suggest that GDF15 modulates the counterregulatory response to hypoglycemia in both PBH individuals and mice and that elevated GDF15 levels contribute to hypoglycemia-related postprandial symptoms. This study was registered at ClinicalTrials.gov (NCT04428866).

Keywords:  GDF15; counterregulatory response; hypoglycemia; hypoglycemia symptoms; post-bariatric hypoglycemia

DOI:  https://doi.org/10.1016/j.xcrm.2026.102656
Front Immunol. 2026 ;17 1747401

Roles of the integrated stress response in regulation of inflammatory reactions.

Fan Jiang, Guei-Sheung Liu, Junjun Liu, Xiaopei Cui, Yanqiu Xing.

  The integrated stress response (ISR) is a conserved cyto-protective mechanism, which has fundamental roles in maintaining cell viability under various conditions when intracellular and/or extracellular homeostasis is disrupted. ISR features phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α), leading to a global reduction in protein synthesis. Emerging evidence suggests that activation of ISR may have anti-inflammatory effects. In this concise review, we summarize the current experimental evidence in this regard from both in vitro and in vivo studies. It is suggested that ISR may represent a potential drug target for developing novel anti-inflammatory therapies.

Keywords:  ATF4; GADD34; anti-inflammation; eIF2a; inflammatory disease; integrated stress response; phosphorylation; protein translation

DOI:  https://doi.org/10.3389/fimmu.2026.1747401
Cell Rep. 2026 Mar 12. pii: S2211-1247(26)00165-8. [Epub ahead of print]45(3): 117087

Targeting the DSTYK-ULK1 axis rewires TNFR1 signaling to overcome treatment resistance in lung cancer.

Andrea Pasquier, Cristina Viu-Idocin, Andrea Arricibita, Mirari Echepare, Beñat Picabea, Daniel Orive, Ane Álava, Joaquín Fernández-Irigoyen, Enrique Santamaría, Allan Argueta, Eva Molina, Antonio Pineda-Lucena, Marco Gentili, Federica Facchinetti, Luca Roz, Luis M Montuenga, Karmele Valencia.

  Immunotherapy has transformed the treatment of non-small cell lung cancer (NSCLC). Yet, acquired resistance remains a major clinical challenge. Defining molecular determinants of tumor sensitivity to T cell-mediated killing is therefore critical. Tumor necrosis factor α (TNF-α) released by cytotoxic T cells promotes tumor cell death, whereas NF-κB signaling supports survival. Autophagy counteracts TNFα-induced apoptosis, and its inhibition enhances responses to immune checkpoint inhibitors (ICIs). Genomic alterations further contribute to immune evasion and reduced immunotherapy efficacy. We previously identified DSTYK, a dual serine/threonine and tyrosine kinase amplified in NSCLC, as a suppressor of TNF-α-mediated CD8+ T cell killing and a driver of ICI resistance through autophagy. Here, we show that DSTYK modulates TNFR1 signaling by phosphorylating the autophagy initiator ULK1, which enables ULK1-dependent phosphorylation of RIPK1. Loss of DSTYK disrupts ULK1 activation, promotes RIPK1 autophosphorylation, proapoptotic signaling, and impaired NF-κB-dependent survival. These findings define a DSTYK-ULK1-RIPK1 axis controlling TNF-α-induced apoptosis and support targeting ULK1 to sensitize DSTYK-amplified NSCLC to T cell-mediated killing.

Keywords:  CP: cancer; CP: immunology; DSTYK; RIPK1; TNFR1 pathway; ULK1; apoptosis; autophagy; lung cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117087
iScience. 2026 Mar 20. 29(3): 115023

Association between elevated expression of GDF15/GFRAL and sarcopenia risk.

Zong-Sheng Zhang, Pei-Dong Fan, Wen-Ya Zhang, Hao-Qi Zou, Jin-Dong Ni, Xin-Ling Yang, Jun Wu.

  Glial cell line-derived neurotrophic factor family receptor α-like (GFRAL) is the exclusive receptor for growth differentiation factor 15 (GDF15) and plays distinct roles in various diseases. However, its impact on sarcopenia remains poorly understood. This study, including White British and Chinese participants, demonstrated that elevated serum levels of GDF15 and its receptor GFRAL are associated with an increased risk of sarcopenia, particularly among individuals with low physical performance. While GDF15 exerts effects across the whole population, GFRAL appears to be more detrimental in women. Complementary single-cell RNA sequencing and immunohistochemical analyses in animal models further support the involvement of the GDF15-GFRAL axis in mediating skeletal muscle damage. These findings highlight the clinical and preventive relevance of the GDF15-GFRAL axis and underscore the need for future mechanistic studies to elucidate its role in sarcopenia.

Keywords:  health sciences

DOI:  https://doi.org/10.1016/j.isci.2026.115023
FASEB J. 2026 Mar 31. 40(6): e71652

Weight Loss During Obesity Provokes Asparaginase-Associated Liver Steatosis and Endoplasmic Reticulum Stress.

Chintan T Bhavsar, Brian A Zalma, Keigo Tomoo, Yi Zhang, Esther M Lopez, Emily T Mirek, Joseph L Dixon, Gregory C Henderson, Ronald C Wek, Tracy G Anthony.

  Asparaginase is an anti-leukemic agent that triggers severe adverse metabolic events. Obesity is a known risk factor for asparaginase-associated liver steatosis. To better understand why, we first compared the liver metabolome of lean versus diet-induced obese (DIO) mice exposed to native asparaginase and observed a substantially altered liver metabolome in DIO mice only. To explore the basis for the altered liver metabolome in DIO mice, we designed experiments to clarify the relative contributions of obesity versus feeding excessive fat during asparaginase on liver triglycerides. Lean mice and DIO mice were fed a high-fat, obesogenic diet (OD) or low fat, maintenance diet (MD) during exposure to pegylated (PEG)-asparaginase. In lean mice, feeding OD during PEG-asparaginase modestly (2-fold) increased liver steatosis. Obese mice fed OD during PEG-asparaginase showed the lowest food intake alongside the lowest liver triglyceride secretion rates, resulting in the largest (6-fold) increase in liver triglycerides and emergent endoplasmic reticulum (ER) stress. Switching obese mice to a MD during PEG-asparaginase did not rescue liver steatosis nor alleviate ER stress. In a separate study, DIO mice globally lacking albumin (AlbKO) were fed OD during exposure to PEG-asparaginase to examine if loss of the major plasma free fatty acid carrier could lessen liver steatosis, but loss of circulating albumin did not mitigate elevated liver triglycerides. In total, the results revealed that body weight loss enables asparaginase-associated liver steatosis and ER stress. Mitigating asparaginase-induced weight loss may be a meaningful strategy in preventing liver stress during treatment.

Keywords:  PERK; free fatty acids; gene expression; lipoproteins

DOI:  https://doi.org/10.1096/fj.202503617RR