bims-stacyt 2025-08-31 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–08–31
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Physical Activity, Exerkines, and Their Role in Cancer Cachexia.
The Multifaceted Role of Growth Differentiation Factor 15 (GDF15): A Narrative Review from Cancer Cachexia to Target Therapy.
Adipocyte-derived factors induce adherent to suspension transition in breast and pancreatic cancer cells through lipid metabolic alteration.
Intracellular Interleukin-1α in Peritumoral Monocytes Induces IL8 Production and Inhibits Mitophagy to Promote Stemness and Metastasis of Hepatocellular Carcinoma.
α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
Ruxolitinib alleviated muscle atrophy in cancer cachexia by inhibiting IL-6/JAK/STAT3 signaling pathway in mice.
The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.
Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment.

Int J Mol Sci. 2025 Aug 19. pii: 8011. [Epub ahead of print]26(16):

Physical Activity, Exerkines, and Their Role in Cancer Cachexia.

Jan Bilski, Aleksandra Szlachcic, Agata Ptak-Belowska, Tomasz Brzozowski.

  Cancer-associated cachexia is a multifaceted wasting syndrome characterized by progressive loss of skeletal muscle mass, systemic inflammation, and metabolic dysfunction and is particularly prevalent in gastrointestinal cancers. Physical activity has emerged as a promising non-pharmacological intervention capable of attenuating key drivers of cachexia. Exercise modulates inflammatory signaling (e.g., IL-6/STAT3 and TNF-α/NF-κB), enhances anabolic pathways (e.g., IGF-1/Akt/mTOR), and preserves lean body mass and functional capacity. Exercise-induced signaling molecules, known as exerkines, are key mediators of these benefits, which are released during physical activity and act in an autocrine, paracrine, and endocrine manner. However, many of these molecules also exhibit context-dependent effects. While they exert protective, anti-inflammatory, or anabolic actions when transiently elevated after exercise, the same molecules may contribute to cachexia pathogenesis when chronically secreted by tumors or in systemic disease states. The biological effects of a given factor depend on its origin, timing, concentration, and physiological milieu. This review presents recent evidence from clinical and experimental studies to elucidate how physical activity and exerkines may be harnessed to mitigate cancer cachexia, with particular emphasis on gastrointestinal malignancies and their unique metabolic challenges.

Keywords:  cancer cachexia; context-dependent signaling; exerkines; gastrointestinal cancers; metabolic dysfunction; physical activity; skeletal muscle; systemic inflammation

DOI:  https://doi.org/10.3390/ijms26168011
Biomedicines. 2025 Aug 08. pii: 1931. [Epub ahead of print]13(8):

The Multifaceted Role of Growth Differentiation Factor 15 (GDF15): A Narrative Review from Cancer Cachexia to Target Therapy.

Daria Maria Filippini, Donatella Romaniello, Francesca Carosi, Laura Fabbri, Andrea Carlini, Raffaele Giusti, Massimo Di Maio, Salvatore Alfieri, Mattia Lauriola, Maria Abbondanza Pantaleo, Lorena Arribas, Marc Oliva, Paolo Bossi, Laura Deborah Locati.

  Background: Growth Differentiation Factor 15 (GDF15) has emerged as a key biomarker and therapeutic target in oncology, with roles extending beyond cancer cachexia. Elevated GDF15 levels correlate with poor prognosis across several solid tumors, including colorectal, gastric, pancreatic, breast, lung, prostate, and head and neck cancers. GDF15 modulates tumor progression through PI3K/AKT, MAPK/ERK, and SMAD2/3 signaling, thereby promoting epithelial-to-mesenchymal transition, metastasis, immune evasion, and chemoresistance via Nrf2 stabilization and oxidative stress regulation. Methods: We performed a narrative review of the literature focusing on the role of GDF15 in solid tumors, with a particular emphasis on head and neck cancers. Results: In head and neck squamous cell carcinoma (HNSCC), GDF15 overexpression is linked to aggressive phenotypes, radioresistance, poor response to induction chemotherapy, and failure of immune checkpoint inhibitors (ICIs). Similar associations are observed in colorectal, pancreatic, and prostate cancer, where GDF15 contributes to metastasis and therapy resistance. Targeting the GDF15-GFRAL axis appears therapeutically promising: the monoclonal antibody ponsegromab improved cachexia-related outcomes in the PROACC-1 trial, while visugromab combined with nivolumab enhanced immune response in ICI-refractory tumors. Conclusions: Further investigation is warranted to delineate the role of GDF15 across malignancies, refine patient selection, and evaluate combinatorial approaches with existing treatments.

Keywords:  GDF15; GFRAL; cachexia; cancer biomarker; chemotherapy resistance; head and neck cancer

DOI:  https://doi.org/10.3390/biomedicines13081931
Sci Rep. 2025 Aug 20. 15(1): 30552

Adipocyte-derived factors induce adherent to suspension transition in breast and pancreatic cancer cells through lipid metabolic alteration.

Doru Kwon, Hyun Woo Park, Byung Soh Min, Junjeong Choi.

  Adipocytes play a dynamic role in the tumor microenvironment (TME) by acting as facilitators, providing cytokines and metabolites that regulate cancer progression and metastasis. Despite metastasis being a major contributor to cancer-associated mortality, our understanding of how adipocytes influence this process remains limited. This study aims to elucidate the regulatory mechanism of Adherent to Suspension Transition (AST) reprogramming within the adipocyte, driven by anchorage dependency. AST facilitates the conversion of adherent tumor cells into suspension cells, thereby contributing to the generation of circulating tumor cells (CTCs). We have evaluated generating AST cells from primary tumors using a dissemination assay that mimics CTCs in vitro. Additionally, we examined AST cell formation when incubated with human adipocyte-conditioned media (ADCM) using the InCucyte live-cell imaging system. Through this approach, we effectively assessed the impact of the tumor-adipocyte interactions on CTC formation from the perspective of AST. As a metastasis-initiating marker, CD36 is pivotal in fatty acid (FA) acquisition and regulates lipid metabolic remodeling during the AST. The generation of AST cells through AST reprogramming is controlled by fatty acid oxidation (FAO), and pharmacological blockade of CD36 and FAO significantly reduced AST cell generation. This demonstrates that CD36 plays a key role in the early stages of AST-induced dissemination. Additionally, promoting cancer cell aggressiveness through ADCM enhances metastatic potency and upregulates the expression of AST reprogramming factors. Inhibition of lipid metabolism not only suppresses AST cell formation but also decreases survival in suspension. This indicates that exogenous lipid uptake and FAO via CD36 play crucial roles in the metastasis process, facilitating the dissemination of primary tumors into the bloodstream. Adipocytes contribute to cancer progression by supplying various metabolites to cancer cells. While primary tumors predominantly rely on glucose as a major energy source, cellular remodeling during dissemination shifts metabolic dependency toward lipids. In the TME, where adipocytes are abundant, tumor cells acquire FA through CD36-mediated uptake for metabolic adaptation. This shift to lipid metabolism is essential for AST, and thus, targeting lipid metabolism via inhibition of CD36 and FAO could serve as a potential therapeutic strategy for AST.

Keywords:  AST; Adipocytes; CD36; Circulating tumor cell; Lipid metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41598-025-13309-4
Cancer Res. 2025 Aug 26.

Intracellular Interleukin-1α in Peritumoral Monocytes Induces IL8 Production and Inhibits Mitophagy to Promote Stemness and Metastasis of Hepatocellular Carcinoma.

Yong-Hao Ruan, Wan-Ru Ning, Ai-Qi Huang, Da Jiang, Bai-Xi Zhu, Xing-Chen Liu, Jiang-Ling Gong, Kun Huang, Dong-Ming Kuang, Yan Wu, Limin Zheng.

IL-1α is a potent inflammatory cytokine that is released by cell necrosis and activates IL-1R. More recently, IL-1α has been shown to have intracellular functions. In the current study, we investigated the expression and distinctive role of IL-1α in tumor progression. In hepatocellular carcinoma (HCC) patients, IL-1α levels were significantly upregulated in monocytes in peritumoral regions compared with nontumoral and intratumoral areas. A glycolytic switch mediated the upregulation of IL-1α via NF-κB signaling. The upregulated IL-1α was neither secreted by nor displayed on the cell surface of monocytes; instead, IL-1α translocated into the nucleus to induce the production of IL-8, which effectively enhanced cancer cell stemness and tumor metastasis. Additionally, IL-1α bound to mitochondria to inhibit mitophagy, inducing CA12 expression and macrophage accumulation via the mitochondrial reactive oxygen species-HIF-1α pathway. In accordance, IL-1α expression in peritumoral monocytes was negatively correlated with survival and positively associated with tumor metastasis in HCC patients. Targeting IL-1α+ monocytes or IL-8 effectively inhibited tumor progression and enhanced responsiveness to immune checkpoint blockade therapy in mouse HCC models. Overall, these results revealed an intracellular regulatory role of IL-1α in modifying the pro-tumor functions of monocytes within specific tumor microenvironments and pointed to both IL-1α and its downstream IL-8 as potential diagnostic and therapeutic targets for HCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3355
Nat Chem Biol. 2025 Aug 22.

α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.

Wen Mi, Yun Xue, Haohang Yan, Yurou Zhang, Xinlei Cai, Shuyuan Zhang, Ruiping He, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Yifan Liang, Chongwen Cao, Yi Xu, Junfeng Bi, Guanlin Wang, Li Chen, Dan Ye, Fei Li, Ruobing Ren, Pingyu Liu, Hongbin Ji, Fuming Li.

The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG-YBX1-dependent AMPK translation can sensitize human cancer cells to energy stress for treatment.

DOI: https://doi.org/10.1038/s41589-025-02013-z
J Pharm Pharmacol. 2025 Aug 20. pii: rgaf073. [Epub ahead of print]

Ruxolitinib alleviated muscle atrophy in cancer cachexia by inhibiting IL-6/JAK/STAT3 signaling pathway in mice.

Cong Li, Xiaofan Gu, Zixia Zhu, Xiaojuan Pan, Meng Fan, Xuan Liu, Xiongwen Zhang.

   OBJECTIVES: Ruxolitinib (Rux), an oral Janus tyrosine Kinase (JAK) tyrosine kinase inhibitor, has demonstrated anti-inflammatory properties and the ability to mitigate denervation-induced skeletal muscle atrophy. Here, we checked the potential efficacy of Rux on cancer cachexia and tried to clarified its mechanisms.
METHODS: The in vitro cell models of C26 or LLC CM-induced C2C12 myotubes were used to check the influence of Rux on myotube atrophy. C26 tumour-bearing mice (male BALB/c mice) were applied as the animal model to examine the effects of Rux in attenuating cachexia symptoms. Western blot analysis was utilized to investigate the potential mechanisms of Rux.
KEY FINDINGS: Rux significantly attenuated C2C12 myotube atrophy in vitro. Rux suppressed the interleukin-6 secretion by inhibiting STAT3 activation in tumour cells and macrophages. The administration of Rux prevented body weight loss and muscle wasting in C26 tumour-bearing mice without affecting tumour growth. At the end of the experiment, mice in the Rux treatment group exhibited a 6.7% increase in body weight compared to the C26 model group. Furthermore, Rux enhanced in gastrocnemius myofibres cross-sectional area and grip strength.
CONCLUSIONS: Rux ameliorates cancer cachexia muscle atrophy by inhibiting STAT3/Atrogin-1 signaling. Rux may represent a promising therapeutic candidate for the treatment of cancer cachexia.

Keywords:  IL-6/JAK/STAT3; Rux; cancer cachexia; macrophages; muscle atrophy; systemic inflammatory response

DOI:  https://doi.org/10.1093/jpp/rgaf073
Cell Commun Signal. 2025 Aug 20. 23(1): 374

The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.

Jiayi E Wang, Charanya Muralidharan, Armando A Puente, Titli Nargis, Jacob R Enriquez, Ryan M Anderson, Raghavendra G Mirmira, Sarah A Tersey.

  Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells. Macrophages infiltrate islets early in T1D pathogenesis, preceding the influx of T- and B-lymphocytes. The integrated stress response (ISR), a cellular pathway activated during stress, coordinates adaptive changes in gene expression to maintain cell function and survival. To study the ISR in macrophages, bone-marrow-derived macrophages were treated with a pharmacological inhibitor of the ISR (ISRIB) and polarized to a proinflammatory M1-like state. We observed a reduction in the number of proinflammatory macrophages, as well as a decrease in iNOS mRNA and protein levels, following ISRIB treatment. RNA-sequencing revealed a reduction in pathways related to stress responses, including ER stress, reactive oxygen species (ROS) regulation, and autophagy, as well as migration pathway genes. ISRIB treatment led to decreased macrophage migration after stimulation in vitro and reduced migration of macrophages to the site of injury after tailfin injury in zebrafish in vivo. Interestingly, ISRIB mediated reduction of M1-like macrophages and reduction of migration was recapitulated by the inhibition of PKR but not PERK, both upstream ISR kinases, highlighting PKR as a key mediator of the ISR in macrophages. Pre-diabetic female non-obese diabetic (NOD) mice administered ISRIB demonstrated an overall reduction in the macrophage numbers in the pancreatic islets. Additionally, the insulitic area of pancreata from ISRIB treated NOD mice had increased PD-L1 levels. PD-L1 protein but not mRNA levels were increased in M1-like macrophages after ISR and PKR inhibition. Our findings identify the ISR, particularly via PKR, as a critical regulator of macrophage driven inflammation and migration in T1D. Our study offers new insights into ISR signaling in macrophages, demonstrating that the ISR may serve as a potential target for intervention in macrophages during early T1D pathogenesis.

Keywords:  Diabetes; Inflammation; Integrated stress response (ISR); Macrophages; Migration; Pancreatic islet; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1186/s12964-025-02372-z
Nat Metab. 2025 Aug 22.

Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment.

Nannan Xu, Yemin Zhu, Yichao Han, Qi Liu, Lingfeng Tong, Yakui Li, Zhangbing Chen, Sijia Shao, Wenrui He, Mingrui Li, Yi Wang, Siyuan Qiang, Peiwei Chai, Peng Du, Wenyi Zhao, Lifang Wu, Ping Zhang, Jianli He, Hecheng Li, Jinke Cheng, Renbing Jia, Bin Li, Ying Lu, Xuemei Tong.

In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg cells, loss of MondoA enhanced CD8+ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA-TXNIP axis, which impaired TCR/CD28-signal-induced CD8+ T cell activation. Importantly, targeting the MondoA-TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA-TXNIP axis is a promising therapeutic target for improving cancer immunotherapy.

DOI: https://doi.org/10.1038/s42255-025-01347-1