bims-stacyt 2025-08-17 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–08–17
nineteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development.
ATF6 Alleviates Endothelial Inflammation Following Extended Hepatectomy Through Inhibition of TRIM10/NF-κB Signaling.
GCN2 regulates paclitaxel-induced neuropathic pain.
Molecular Links Between Metabolism and Mental Health: Integrative Pathways from GDF15-Mediated Stress Signaling to Brain Energy Homeostasis.
Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling.
Exercise Duration Modulates Cortisol Release and Chronic Cortisol Exposure Jeopardises T Cell Effector Functions.
Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models.
JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance.
The glycosyltransferase ALG3 is an AKT substrate that regulates protein N-glycosylation.
Pharmacological but Not Physiological Levels of GDF15 and FGF21 Regulate Body Weight and Glycemic Control in Obese Mice.
Divergent glucose stress responses in TM4 Sertoli cells: a miRNA-driven regulatory landscape of inflammation and cytokine expression.
MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts.
Polysialylation of Glioblastoma Cells Is Regulated by Autophagy Under Nutrient Deprivation.
Pan-cancer analysis implicates novel insights of cholesterol biosynthesis into immunotherapy response prediction and survival prognostication.
Linking tumour angiogenesis and tumour immunity.
IL-6 promotes metastasis and EMT of non-small cell lung cancer cells by up-regulating FGL1 via STAT3 pathway.
Enhancement of anti-programmed cell death protein-1 immunotherapy in non-small cell lung cancer using arginine and citrulline supplementation.
Asparaginase Enhances CAR-T Cell Antitumor Immunity by Asparagine Metabolic Reprogramming and Induction of Central Memory Phenotype in ALL.
Cytokine response to critical illness and its relation to amino acid metabolism.

Cell Metab. 2025 Aug 06. pii: S1550-4131(25)00335-3. [Epub ahead of print]

Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development.

Yihao Liu, Jiayu Lin, Zhengwei Yu, Xueying Li, Xueqi Lv, Pengyi Liu, Xiuqiao Sun, Zhen Zhang, Xia Gao, Keyan Sun, Dan Li, Jingfeng Li, Yang Liu, Yu Jiang, Siyi Zou, Jianping Lin, Baofa Sun, Da Fu, Baiyong Shen.

  Diabetes mellitus (DM) is a known risk factor for pancreatic cancer, but the underlying mechanisms remain elusive. Here, we identify lactate-driven remodeling of tumor-associated Schwann cells (TASCs) as a key mediator of immunosuppression in diabetic pancreatic ductal adenocarcinoma (PDAC). Single-cell RNA sequencing revealed a c1-Mettl16+Cd276+Nectin2+ TASC subpopulation enriched in diabetic tumors that impairs CD8+ T cell function and promotes PD-1 resistance. Mechanistically, lactate enters TASCs via MCT1/MCT4, binds METTL16, and induces K269 lactylation, enhancing m6A-dependent CTCF stabilization and transcriptional activation of immunosuppressive ligands. Targeting METTL16 restores immune surveillance and sensitizes tumors to PD-1 blockade. Retrospective analyses confirmed therapeutic benefit in patients with diabetic PDAC receiving rosuvastatin. These findings uncover a lactate-METTL16-CTCF axis that links metabolic stress to epitranscriptomic reprogramming and immune evasion, offering a promising strategy to potentiate immunotherapy in metabolically dysregulated PDAC.

Keywords:  METTL16; anti-tumor immune response; diabetes-associated pancreatic cancer; lactate sensing; rosuvastatin, anti-PD-1; tumor-associated Schwann cells

DOI:  https://doi.org/10.1016/j.cmet.2025.07.008
FASEB J. 2025 Aug 31. 39(16): e70933

ATF6 Alleviates Endothelial Inflammation Following Extended Hepatectomy Through Inhibition of TRIM10/NF-κB Signaling.

Cheng-Cheng Shi, Dong-Jing Yang, Yang Bai, Binhui Zhou, Yao-Hui Sun, Xiao-Ran Xu, Wen-Zhi Guo, Shui-Jun Zhang, Yinming Liang, Yang Jin, Ji-Hua Shi.

  The inflammatory response in liver sinusoidal endothelial cells (LSECs) is crucial to the pathophysiology of postoperative hepatic failure. The unfolded protein response (UPR) in LSECs following surgical stress exerts an important mechanism for resolving endothelial inflammation and re-establishing liver homeostasis. We employed 80% hepatectomy in mice to simulate extended hepatectomy and verified the gene expression in the patients who underwent marginal hepatectomy. The UPR in LSECs and endothelial inflammation were induced with tunicamycin or lipopolysaccharides in HUVECs to investigate the expression, effect, and regulation of activating transcription factor 6 (ATF6) in endothelial inflammation. We found that UPR protein ATF6 in LSECs was upregulated and activated following extended hepatectomy in both mice and humans; ATF6 deficiency in mice by either global knockout or LSECs-specific knockdown failed to alleviate the inflammatory response and led to severe liver injury; genetic knockout or pharmacological inhibition of ATF6 by the ATF6 antagonist Ceapin-A7 in HUVECs led to severe inflammation through the nuclear factor-κB (NF-κB) signaling pathway, while the ATF6 agonist AA147 ameliorated inflammation. Mechanistically, ATF6 induced negative transcriptional control of tripartite motif-containing protein 10 (TRIM10) and the downstream NF-κB signaling pathway, thereby suppressing endothelial inflammation. Taken together, our data identify ATF6 as a suppressor of endothelial inflammation following extended hepatectomy and clarify the underlying regulatory mechanism of the ATF6-TRIM10/NF-κB signaling pathway. These findings highlight its potential as a therapeutic target for postoperative hepatic failure.

Keywords:  liver sinusoidal endothelial cell; postoperative hepatic failure; tripartite motif‐containing protein 10; unfolded protein response activating transcription factor 6

DOI:  https://doi.org/10.1096/fj.202402197RRR
Br J Pharmacol. 2025 Aug 13.

GCN2 regulates paclitaxel-induced neuropathic pain.

Alexander R Mikesell, Angela R Meyer, Guadalupe García, Luke R Frietze, Cheryl L Stucky, Tao Pan, Zachary T Campbell.

   BACKGROUND AND PURPOSE: Neuropathic pain is debilitating and pervasive. Chemotherapeutic agents commonly induce chronic neuropathic pain. Paclitaxel is a prototypical example, causing painful peripheral neuropathy in a majority of patients. Paclitaxel triggers persistent changes in the excitability of sensory neurons resulting in hypersensitivity to sensory cues. The molecular mechanisms underlying paclitaxel-induced maladaptive plasticity are unclear. Here, we demonstrate a role for the Integrated Stress Response (ISR)-a key translational control mechanism-and its activating kinase, general control non-derepressible 2 kinase (GCN2), in paclitaxel-induced neuropathic pain (PINP).
EXPERIMENTAL APPROACH: We used genetic and pharmacological techniques, including sensory neuron-specific GCN2 conditional knockout mice and the selective GCN2 inhibitor GCN2-IN-7. Behavioural assays assessed mechanical and cold hypersensitivity, while primary DRG neuron cultures were used to evaluate neuronal excitability via calcium imaging and protein translation by puromycin incorporation (surface sensing of translation, SUnSET). tRNA charging and abundance were measured using MSR-seq.
KEY RESULTS: Paclitaxel robustly activated the ISR via GCN2 in mouse DRG sensory neurons, shown by increased eIF2α phosphorylation, elevated ATF4 levels and reduced global translation rates. Genetic deletion or pharmacological inhibition of GCN2 blocked paclitaxel-induced sensory neuron sensitisation and significantly attenuated mechanical and cold hypersensitivity in vivo. Mechanistically, paclitaxel reduced global tRNA charging and abundance in DRGs, providing a molecular basis for GCN2 activation.
CONCLUSIONS AND IMPLICATIONS: These findings demonstrate that GCN2-dependent ISR activation is critical for PINP. Targeting GCN2 may represent a promising therapeutic strategy for preventing or alleviating chemotherapy-induced peripheral neuropathy, potentially improving patient quality of life and chemotherapy tolerance.

Keywords:  GCN2; ISR; PINP; eIF2

DOI:  https://doi.org/10.1111/bph.70154
Int J Mol Sci. 2025 Aug 06. pii: 7611. [Epub ahead of print]26(15):

Molecular Links Between Metabolism and Mental Health: Integrative Pathways from GDF15-Mediated Stress Signaling to Brain Energy Homeostasis.

Minju Seo, Seung Yeon Pyeon, Man S Kim.

  The relationship between metabolic dysfunction and mental health disorders is complex and has received increasing attention. This review integrates current research to explore how stress-related growth differentiation factor 15 (GDF15) signaling, ceramides derived from gut microbiota, and mitochondrial dysfunction in the brain interact to influence both metabolic and psychiatric conditions. Evidence suggests that these pathways converge to regulate brain energy homeostasis through feedback mechanisms involving the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. GDF15 emerges as a key stress-responsive biomarker that links peripheral metabolism with brainstem GDNF family receptor alpha-like (GFRAL)-mediated anxiety circuits. Meanwhile, ceramides impair hippocampal mitochondrial function via membrane incorporation and disruption of the respiratory chain. These disruptions may contribute to sustained pathological states such as depression, anxiety, and cognitive dysfunction. Although direct mechanistic data are limited, integrating these pathways provides a conceptual framework for understanding metabolic-psychiatric comorbidities. Furthermore, differences in age, sex, and genetics may influence these systems, highlighting the need for personalized interventions. Targeting mitochondrial function, GDF15-GFRAL signaling, and gut microbiota composition may offer new therapeutic strategies. This integrative perspective helps conceptualize how metabolic and psychiatric mechanisms interact for understanding the pathophysiology of metabolic and psychiatric comorbidities and highlights therapeutic targets for precision medicine.

Keywords:  GDF15; anxiety; biomarkers; depression; gut–brain axis; mental health; metabolism; mitochondria; precision medicine; stress

DOI:  https://doi.org/10.3390/ijms26157611
bioRxiv. 2025 Jul 14. pii: 2025.07.09.663949. [Epub ahead of print]

Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling.

Jacob R Beal, Xiangning Song, Athilakshmi Kannan, Indrani C Bagchi, Milan K Bagchi.

During early pregnancy, human endometrial stromal cells differentiate into secretory decidual cells via a process regulated by ovarian steroid hormones. Decidual cells play a crucial role by secreting various factors that support essential events in forming a functional placenta, including uterine angiogenesis and the differentiation and development of trophoblasts. We previously reported that the conditional ablation of the transcription factor RUNX1 in the mouse uterus leads to subfertility due to insufficient maternal angiogenesis and impaired trophoblast differentiation. In this study, we examined the role of RUNX1 in facilitating communication mechanisms among human decidual cells and other cell types present in the pregnant uterus. We demonstrated that RUNX1 regulates the conserved HIF2α-RAB27B pathway in primary human endometrial stromal cells (HESC) during decidualization, which promotes the secretion of extracellular vesicles (EVs) by these cells. Consequently, the depletion of RUNX1 in HESC led to reduced EV secretion. Mass spectrometry identified several cargo proteins in decidual EVs, including ANGPTL2 and IGF2, which could regulate angiogenesis or trophoblast differentiation. We found that RUNX1 directly regulates their expression, resulting in partial changes to these cargoes when it is absent. We observed that delivering EVs lacking ANGPTL2 or IGF2 to human endothelial cells significantly decreased the formation of vascular networks compared to introducing control EVs carrying these factors. Furthermore, adding IGF2-depleted EVs to human trophoblast cells inhibited their differentiation into the extravillous trophoblast lineage. These findings collectively highlight the crucial role of decidual RUNX1 in promoting essential cell-cell interactions for angiogenesis and trophoblast differentiation during placenta formation.

DOI: https://doi.org/10.1101/2025.07.09.663949
Immunology. 2025 Aug 12.

Exercise Duration Modulates Cortisol Release and Chronic Cortisol Exposure Jeopardises T Cell Effector Functions.

Thy Viet Luu, Line Fleischer Hach, Tina Seremet, Katharina Leuchte, Per Thor Straten, Gitte Holmen Olofsson.

  Psychological stress has been linked to increased incidence and mortality of cancer. During stress, cortisol is released into circulation and regulates cellular processes including immune activity by acting on glucocorticoid receptors (GCRs) expressed by target cells. Chronic stress-induced cortisol has been suggested to promote tumour progression and compromise the efficacy of cancer treatments. Conversely, cortisol is also transiently secreted during exercise. Although exercise has been suggested to have beneficial effects against cancer, the impact of exercise-elevated cortisol on immune cell functions remains poorly understood. Here we studied the dynamics of cortisol secretion following exercise and how cortisol affects effector functions of T cells in the context of acute versus chronic stress. We show that 40 min of acute, high-intensity exercise in healthy adults significantly increased stable circulating cortisol levels whereas a 5-min sprint failed to. Acute exposure to cortisol for 4 h showed no negative effects on the proliferation, cytokine release, or killing activity of human CD3+ T cells. In contrast, chronic cortisol dampened these T cell effector functions. Furthermore, chronic cortisol exposure induced the proliferation of several cancer cell lines. Our findings highlight the opposing effects of cortisol during acute stress, such as exercise, compared to chronic stress, on cancer cells and T cells. This suggests an important potential in targeting cortisol signalling to enhance cancer immunotherapy.

Keywords:  T cell; cancer; neuroimmunology; regulation/suppression

DOI:  https://doi.org/10.1111/imm.70028
J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70044

Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models.

Pooreum Lim, Sang Woo Woo, Jihye Han, Young Lim Lee, Jin Ju Lim, Yeong Hoon Kang, Ji Wook Moon, Jeong Min Nam, Jeong Hyeon Kim, Donghun Kim, Jae Ho Shim, Hyeon Soo Kim.

   BACKGROUND: Cancer-associated cachexia (CAC) is a multifactorial syndrome characterised by progressive loss of muscle mass with limited Food and Drug Administration treatments. Although emerging evidence suggests that l-leucine and β-hydroxy-β-methyl butyrate (HMB) have potential for treating CAC, the role of α-ketoisocaproate (KIC), a metabolite of l-leucine, remains unclear. Therefore, this study explored the use of KIC as a therapeutic agent for CAC-induced muscle atrophy by targeting myostatin.
METHODS: We evaluated the effect of KIC on muscle atrophy using BALB/c mice and C2C12 myotubes as models of C26- and 4T1-induced CAC. Male and female mice were injected with C26 and 4T1 cells, respectively. Grip strength was measured weekly, and mice were sacrificed 4 weeks post-injection for muscle collection. C2C12 myotubes were treated with conditioned media (CM) derived from C26 or 4T1 cells.
RESULTS: KIC suppressed mRNA expression of myostatin, a key regulator of muscle atrophy, more effectively than did l-leucine (-26.37 ± 4.11%, p < 0.01). KIC enhanced protein turnover in C2C12 myotubes and maintained 50% cell viability at high concentrations (KIC: 4.68 mM, HMB: 3.11 mM). Following CM treatment, KIC suppressed MuRF1 and MAFbx expression in a myostatin-dependent manner, thereby reducing their polyubiquitination. KIC restored Akt-FoxO3a phosphorylation, leading to improved myotube diameter (+63.8 ± 25.71%, p < 0.05) and fusion index (+51.9 ± 22.6%, p < 0.05). Immunofluorescence and nuclear fractionation revealed that KIC reduced FoxO3a nuclear accumulation. CM reduced p-Akt-FoxO3a interaction, which was rescued by KIC. In vivo, KIC administration increased body weight (11.11 ± 8.53%), grip strength (24.76 ± 10.58%), and skeletal muscle mass (p < 0.001) in C26 tumour-bearing mice. Protein expression of myostatin in the tibialis anterior (TA) muscle (-23.57 ± 12.22%, p < 0.05) and serum (-52.11 ± 3.56%, p < 0.001) was lower in KIC-treated mice (n = 12) compared with that in the controls. KIC increased the mean fibre cross-sectional area in TA (24.51 ± 14.14%, p < 0.01). In 4T1 tumour-bearing mice, KIC improved body weight (13.10 ± 10.76%) and grip strength (7.42 ± 4.33%) (p < 0.001, n = 10). Serum myostatin levels (-57.43 ± 9.46%, p < 0.001) and skeletal muscle weight were reduced in KIC-treated mice (n = 10).
CONCLUSION: Our findings demonstrate that KIC improves muscle function in CAC-induced muscle atrophy by regulating myostatin expression in skeletal muscle via the Akt-FoxO3a pathway. Thus, KIC has been proposed as a potential therapeutic agent against CAC.

Keywords:  Akt; FoxO3a; alpha‐ketoisocaproate; cancer cachexia; myostatin; protein turnover

DOI:  https://doi.org/10.1002/jcsm.70044
Cells. 2025 Aug 02. pii: 1194. [Epub ahead of print]14(15):

JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance.

Chunyan Zhang, Jieun Song, Wang Zhang, Rui Huang, Yi-Jia Li, Zhifang Zhang, Hong Xin, Qianqian Zhao, Wenzhao Li, Saul J Priceman, Jiehui Deng, Yong Liu, David Ann, Victoria Seewaldt, Hua Yu.

  Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance.

Keywords:  JAK2/STAT3; inflammation; insulin resistance; obesity

DOI:  https://doi.org/10.3390/cells14151194
J Biol Chem. 2025 Aug 09. pii: S0021-9258(25)02433-0. [Epub ahead of print] 110582

The glycosyltransferase ALG3 is an AKT substrate that regulates protein N-glycosylation.

Adrija J Navarro-Traxler, Laura Ghisolfi, Evan C Lien, Alex Toker.

  The PI3K/AKT signaling pathway is frequently dysregulated in cancer and controls key cellular processes such as survival, proliferation, metabolism and growth. Protein glycosylation is essential for proper protein folding and is also often deregulated in cancer. Cancer cells depend on increased protein folding to sustain oncogene-driven proliferation rates. The N-glycosyltransferase asparagine-linked glycosylation 3 homolog (ALG3), a rate-limiting enzyme during glycan biosynthesis, catalyzes the addition of the first mannose to glycans in an alpha-1,3 linkage. Here we show that ALG3 is phosphorylated downstream of the PI3K/AKT pathway in both growth factor-stimulated cells and PI3K/AKT-hyperactive cancer cells. AKT directly phosphorylates ALG3 in the amino terminal region at Ser11/Ser13. CRISPR/Cas9-mediated depletion of ALG3 leads to improper glycan formation and induction of endoplasmic reticulum stress, the unfolded protein response, and impaired cell proliferation. Phosphorylation of ALG3 at Ser11/Ser13 is required for glycosylation of cell surface receptors EGFR, HER3 and E-cadherin. These findings provide a direct link between PI3K/AKT signaling and protein glycosylation in cancer cells.

Keywords:  AKT; ALG3; N-glycosylation; PI3-kinase; glycans; phosphorylation; signaling

DOI:  https://doi.org/10.1016/j.jbc.2025.110582
FASEB J. 2025 Aug 15. 39(15): e70918

Pharmacological but Not Physiological Levels of GDF15 and FGF21 Regulate Body Weight and Glycemic Control in Obese Mice.

Sarah Engelbeen, Julie Mie Jacobsen, Luisa Deisen, Elisa Parsche, Alberte Buch-Ramussen, Christoffer Clemmensen, Rune Ehrenreich Kuhre, Kornelia Johann, Maximilian Kleinert.

  GDF15 and FGF21 are stress-induced hormone-like factors with putative roles in the regulation of energy homeostasis. Since their plasma levels increase with obesity, it has been proposed that GDF15 and FGF21 jointly impose a cap on weight gain during diet-induced obesity. To test this hypothesis, we generated single Gdf15 knockout (KO) and Fgf21 KO, and double Gdf15/Fgf21 KO mice. Depletion of both GDF15 and FGF21 had minimal effects on the gain of body weight, fat, and fat-free mass in male or female mice fed either chow diet or high-fat, high-sucrose diet. Similarly, glucose tolerance, fasting glucose, and plasma insulin levels were largely unaffected by the combined absence of GDF15 and FGF21. Thus, combined deletion of endogenous Gdf15 and Fgf21 exerted a limited influence on body weight gain or glycaemic control. By contrast, pharmacological dosing of obese male mice with long-acting recombinant GDF15 or FGF21 produced meaningful weight loss on their own (8%-10%), and GDF15 + FGF21 co-administration yielded an impressive, additive weight reduction of 25%. Combinatorial treatment also improved glucose tolerance, lowered fasting insulin levels, and reduced hepatic fat content. In conclusion, while endogenous GDF15 and FGF21 appear largely nonessential for the regulation of weight gain and glycemia, pharmacological co-treatment with GDF15 and FGF21 elicits robust weight-loss benefits.

Keywords:  FGF21; GDF15; diet‐induced obesity; energy homeostasis regulation; gene knockout mice; glucose tolerance; pharmacological weight‐loss therapy

DOI:  https://doi.org/10.1096/fj.202501350R
Mol Biol Rep. 2025 Aug 11. 52(1): 817

Divergent glucose stress responses in TM4 Sertoli cells: a miRNA-driven regulatory landscape of inflammation and cytokine expression.

Khder H Rasul, Esra O Hameed, Karim J Karim, Sana Moshari, Amir Nahali.

   BACKGROUND: Glucose homeostasis is essential for cellular function in the testis and deviations in glucose levels are triggering profound physiological and pathological changes. Sertoli cells, critical somatic cells for spermatogenesis, are particularly sensitive to metabolic stress, including fluctuations in extracellular glucose levels.
AIMS: The present study explores the consequences of high and low extracellular glucose concentrations on miRNA (miR) expression, inflammatory responses, and cellular viability in TM4 Sertoli cells.
METHODS: TM4 cells were cultured under control (5.5 mM glucose), high (115 mM glucose) and low (< 0.505 mM glucose) conditions and analyzed for miR (miR-155, miR-155-5p, miR-124, and miR-132) expression, anti-and pro-inflammatory cytokine production (IL-1β, IL-6, TNF-α, TGF-β, and IL-10), and cell viability.
RESULTS: Quantitative real-time polymerase chain reaction (qRT-PCR) revealed significant upregulation of miR-155 and miR-155-5p in high- and low-glucose conditions respectively, while low glucose elevated miR-155-5p but suppressed miR-124 expression. Both glucose conditions upregulated miR-132 without significant differences between the two treatments. Pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α were significantly elevated at the mRNA and protein levels and TGF-β at mRNA level in response to glucose stress. Low glucose induced more robust TNF-α and IL-6 responses compared to high glucose, whereas anti-inflammatory IL-10 expression significantly decreased only under low-glucose conditions. Cell viability was reduced under both glucose treatments, with a more pronounced effect in low glucose.
CONCLUSIONS: These findings highlight a glucose-dependent regulatory mechanism in TM4 Sertoli cells, where miRNA expression correlates with inflammatory cytokine profiles. Low glucose amplified pro-inflammatory responses, potentially driven by suppressed miR-124, while high glucose elicited a compensatory anti-inflammatory response with stable IL-10 expression. This study provides insights into the metabolic and inflammatory dynamics of Sertoli cells, emphasizing the role of miRNAs in modulating cellular responses to glucose stress, with implications for understanding diabetic testicular pathophysiology.

Keywords:  Cytokines; Glucose stress; Inflammation; MiRNA; TM4 sertoli cells

DOI:  https://doi.org/10.1007/s11033-025-10918-0
Cell Death Dis. 2025 Aug 09. 16(1): 603

MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts.

Chloé C Lefebvre, Philippine Giowachini, Jennifer Derrien, Maxime Naour, Isabelle Corre, Laura Thirouard, Elise Douillard, David Chiron, François Guillonneau, Lucas Treps, Mario Campone, Philippe P Juin, Frédérique Souazé.

Breast cancer-associated fibroblasts (bCAFs) comprise inflammatory CAFs (iCAFs), characterized by the secretion of pro-inflammatory cytokines, and myofibroblastic CAFs (myCAFs), distinguished by their high production of extracellular matrix and their immunosuppressive properties. We previously showed that targeting the anti-apoptotic protein MCL-1 in primary culture of bCAF derived directly from human samples reduces their myofibroblastic characteristics. We herein show by single-cell RNA-sequencing analysis of bCAFs that MCL-1 knock down induces a phenotypic shift from wound-myCAF to IL-iCAF, characterized by the upregulation of genes associated with inflammation as well as angiogenesis-related genes. In vitro, genetic and pharmacologic MCL-1 inhibition increases VEGF secretion by bCAFs, enhancing endothelial cell tubulogenesis. In a chicken chorioallantoic membrane (CAM) model in ovo, co-engraftment of breast cancer cells and bCAFs with reduced MCL-1 expression leads to heightened peritumoral vascular density, driven by VEGF. Mechanistically, the pro-angiogenic phenotype revealed by MCL-1 inhibition is dependent on BAX-BAK activity. It results in NF-κB activation, inhibition of which by a IKKβ inhibitor suppresses the transcription of VEGF and pro-inflammatory factors triggered by MCL-1 inhibition in bCAFs. Chemotherapy downregulates MCL-1 in bCAFs via an increase of NOXA, the endogenous MCL-1 inhibitor, promoting a pro-angiogenic and inflammatory phenotype through the NOXA/MCL-1/NF-kB axis. Overall, these findings uncover a novel regulatory function of MCL-1 in determining bCAF subpopulation differentiation and highlight its role in modulating their pro-angiogenic properties, in response to treatment in particular.

DOI: https://doi.org/10.1038/s41419-025-07920-6
Int J Mol Sci. 2025 Aug 06. pii: 7625. [Epub ahead of print]26(15):

Polysialylation of Glioblastoma Cells Is Regulated by Autophagy Under Nutrient Deprivation.

Sofia Scibetta, Giuseppe Pepe, Marco Iuliano, Alessia Iaiza, Elisabetta Palazzo, Marika Quadri, Thomas J Boltje, Francesco Fazi, Vincenzo Petrozza, Sabrina Di Bartolomeo, Alba Di Pardo, Antonella Calogero, Giorgio Mangino, Vittorio Maglione, Paolo Rosa.

  Glioblastoma (GBM) is a highly aggressive brain tumor marked by invasive growth and therapy resistance. Tumor cells adapt to hostile conditions, such as hypoxia and nutrient deprivation, by activating survival mechanisms including autophagy and metabolic reprogramming. Among GBM-associated changes, hypersialylation, particularly, the aberrant expression of polysialic acid (PSA), has been linked to increased plasticity, motility, and immune evasion. PSA, a long α2,8-linked sialic acid polymer typically attached to the NCAM, is abundant in the embryonic brain and re-expressed in cancers, correlating with poor prognosis. Here, we investigated how PSA expression was regulated in GBM cells under nutrient-limiting conditions. Serum starvation induced a marked increase in PSA-NCAM, driven by upregulation of the polysialyltransferase ST8SiaIV and an autophagy-dependent recycling of sialic acids from degraded glycoproteins. Inhibition of autophagy or sialidases impaired PSA induction, and PSA regulation appeared dependent on p53 function. Immunohistochemical analysis of GBM tissues revealed co-localization of PSA and LC3, particularly around necrotic regions. In conclusion, we identified a novel mechanism by which GBM cells sustain PSA-NCAM expression via autophagy-mediated sialic acid recycling under nutrient stress. This pathway may enhance cell migration, immune escape, and stem-like properties, offering a potential therapeutic target in GBM.

Keywords:  autophagy; glioblastoma; nutrient deprivation; polysialic acid; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26157625
Comput Biol Med. 2025 Aug 14. pii: S0010-4825(25)01210-7. [Epub ahead of print]196(Pt C): 110859

Pan-cancer analysis implicates novel insights of cholesterol biosynthesis into immunotherapy response prediction and survival prognostication.

Xingwang Zhou, Zhangwei Yan, Jie Yang, Jiaze Tang, Wu Cen, Junshuan Cui, Wei Teng, Yuanguo Ling, Niya Long, Zhiheng Guo, Liangzhao Chu.

  Cancer therapy has been transformed by immune checkpoint inhibitors (ICIs); however, their limited response rates and significant heterogeneity remain major challenges, necessitating continued focus. Targeting cholesterol biosynthesis (CB) in tumor cells has emerged as a promising strategy to enhance anti-tumor immune responses, representing a novel therapeutic approach. To elucidate the relationship between CB and ICI responsiveness, we analyzed publicly accessible single-cell RNA sequencing (scRNA-seq) data from patients treated with ICIs. Our analysis integrated a comprehensive pan-cancer dataset comprising 40 scRNA-seq datasets, 30 Cancer Genome Atlas (TCGA) pan-cancer cohorts, and 9 ICI transcriptomics cohorts. We formulated and validated a novel CB-associated signature (CB.SIG). The therapeutic potential of CB. SIG genes were further explored using 17 CRISPR datasets to identify potential immunotherapy targets. In two scRNA-seq immunotherapy cohorts, the CB score significantly correlated with resistance to immunotherapy. Across the pan-cancer dataset, CB. SIG exhibited a significant negative correlation with the imbalance of anti-tumor immunity and immune cell infiltration, while positively correlated with tumor-promoting pathways. Using CB. SIG, machine learning models predicted immunotherapy response and patient prognosis with the AUC values of 0.73 on both validation and test sets. Notably, CB. SIG outperformed previously reported biomarkers across multiple cancer types. Through CRISPR screening, TNFRSF10B was identified as a pan-cancer biomarker predictive of immunotherapy responsiveness and survival, a finding further supported by spatial transcriptomics and immunohistochemistry datasets. Functional assays indicated that silencing TNFRSF10B reduced proliferation, migration, and invasion while increasing apoptosis in non-small cell lung cancer and breast cancer cells. Overall, CB. SIG performed better in predicting ICI responses than alternative signatures and offers a potent tool for identifying patients suitable for immunotherapy.

Keywords:  Cholesterol biosynthesis; Immunotherapy; Pan-cancer analysis; Survival prognostication; scRNA-seq

DOI:  https://doi.org/10.1016/j.compbiomed.2025.110859
Nat Rev Immunol. 2025 Aug 14.

Linking tumour angiogenesis and tumour immunity.

Ashraf Ul Kabir, Madhav Subramanian, Yoojung Kwon, Kyunghee Choi.

Immune checkpoint blockade therapy has revolutionized the treatment of metastatic and solid tumours, achieving durable responses in a subset of patients. However, most patients do not respond to immune checkpoint blockade, underscoring the critical need to better understand the determinants of therapeutic efficacy. A key obstacle to effective antitumour immune responses is the abnormal structure and function of tumour-associated blood vessels, which impede immune cell infiltration and contribute to the development of an immunosuppressive tumour microenvironment. Current research highlights the inverse correlation between angiogenesis and immune activity within the tumour microenvironment. In this Review, we discuss tumour angiogenesis in the context of tumour immunity, examining how this affects tumour progression and immunotherapy outcomes. We examine the molecular mechanisms underlying the crosstalk between angiogenesis and tumour immunity and discuss emerging anti-angiogenic regulators that hold potential for combination therapies. By integrating insights from preclinical and clinical studies, we outline future research directions to address current challenges and optimize cancer treatment strategies through combined anti-angiogenic and immunotherapeutic approaches.

DOI: https://doi.org/10.1038/s41577-025-01211-z
Transl Cancer Res. 2025 Jul 30. 14(7): 3973-3990

IL-6 promotes metastasis and EMT of non-small cell lung cancer cells by up-regulating FGL1 via STAT3 pathway.

Jing Liu, Qiuge Liu, Wenjing Qian, Chengguo Zong, Ruoyu Wang.

   Background: It has been reported that IL-6 induces the synthesis and secretion of fibrinogen-like protein 1 (FGL1) in liver cells as well as promotes the regeneration of liver cells. FGL1 is upregulated in human cancers, especially in non-small cell lung cancer (NSCLC). FGL1 is involved in the regulation of epithelial-mesenchymal transition (EMT) in gastric cancer (GC) cells. However, the role of IL-6/FGL1 signaling axis in the EMT process of NSCLC cells and its mechanism remain unclear. In this study, we investigated the role of FGL1 in mediating the metastasis and EMT processes of NSCLC cells, as well as the underlying signaling mechanisms.
Methods: The Cancer Genome Atlas (TCGA) database and STARBASE database were used to analyze the biological information of FGL1 gene expression in NSCLC patients, and the database information was verified by clinical data. Transwell, Western blotting and microscopy were used to observe the effects of FGL1 on the metastasis and proliferation of NSCLC cells and the occurrence of EMT and its potential signaling pathway proteins.
Results: Database analysis and clinical data showed that the prognosis of NSCLC patients with high FGL1 expression was poor. Cell phenotypic experiments showed that FGL1 silencing significantly reduced proliferation, migration and EMT of NSCLC cells, suggesting that the expression level of FGL1 may be significantly correlated with migration ability and EMT in lung cancer cells. In addition, the FGL1-neutralizing antibody inhibited EMT and metastasis of NSCLC cells in vivo. Further studies showed that IL-6 may mediate EMT by inducing FGL1 expression through the STAT3 pathway in lung cancer cells. Furthermore, treatment with a STAT3 inhibitor significantly inhibited the IL-6-induced FGL1 expression and EMT in NSCLC cells.
Conclusions: IL-6 regulates FGL1 expression to mediate metastasis and EMT of NSCLC cells through the STAT3 signaling pathway.

Keywords:  IL-6/STAT3; Non-small cell lung cancer (NSCLC); epithelial-mesenchymal transition (EMT); fibrinogen-like protein 1 (FGL1); metastasis

DOI:  https://doi.org/10.21037/tcr-2025-119
J Thorac Dis. 2025 Jul 31. 17(7): 4814-4825

Enhancement of anti-programmed cell death protein-1 immunotherapy in non-small cell lung cancer using arginine and citrulline supplementation.

Naoki Miyamoto, Mitsuteru Yoshida, Shinichi Tsukumo, Hirohisa Ogawa, Tamaki Otani, Koji Yasutomo, Hiromitsu Takizawa.

   Background: Immune checkpoint inhibitors (ICIs) have substantially improved outcomes in previously untreatable cancer cases, but their effectiveness as monotherapies is limited. In this study, we examined the role of citrulline in the lung cancer microenvironment and its potential synergistic effects with immunotherapy.
Methods: Murine lung cancer cells (CMT167) were subcutaneously implanted in mice to establish tumor models, which were then treated with the anti-programmed death 1 (PD-1) antibody either alone or in combination with arginine or arginine and citrulline. Tumor growth, survival rate, cytokine levels, immune cell populations, and metabolic marker expression were assessed using histological, immunostaining, flow cytometry, and serum analyses.
Results: Mice in the treatment groups exhibited significantly lower tumor volumes than those in the control group (control, 1,161.59±294.73 mm3; anti-PD-1, 427.38±355.34 mm3; anti-PD-1 plus arginine, 452.10±332.04 mm3; anti-PD-1 plus arginine and citrulline, 198.45±236.22 mm3; P<0.001). Furthermore, the anti-PD-1 plus arginine and citrulline group exhibited significantly improved progression-free survival compared to the control group (P<0.001). The anti-PD-1 plus arginine and citrulline group also showed a significantly higher number of tumor-infiltrating CD8+ lymphocytes per high-power field (hpf) than the control group (control, 24.22±9.13 cells/hpf; anti-PD-1, 29.20±9.41 cells/hpf; anti-PD-1 plus arginine, 34.33±8.81 cells/hpf; anti-PD-1 plus arginine and citrulline, 46.56±10.01 cells/hpf).
Conclusions: Arginine and citrulline supplementation facilitated CD8+ lymphocyte infiltration into the tumor microenvironment, thereby augmenting the efficacy of lung cancer immunotherapy.

Keywords:  CD8 T cells; Immunotherapy; arginine; citrulline supplementation; non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.21037/jtd-2024-2109
Mol Ther. 2025 Aug 12. pii: S1525-0016(25)00650-1. [Epub ahead of print]

Asparaginase Enhances CAR-T Cell Antitumor Immunity by Asparagine Metabolic Reprogramming and Induction of Central Memory Phenotype in ALL.

Xinting Zhu, Leng Han, Dingyuan Bai, Lei Yi, Yonghong Zhao, Shuaibing Liu, Run Gan, Bo Xin, Yixing Tu, Jianping Zhang, Yonglong Han, Juan Hao, Zixue Xuan, Cheng Guo, Quanjun Yang.

High levels of asparagine synthetase (ASNS) in acute lymphoblastic leukemia (ALL) lead to immunotherapy resistance. Our study showed ASNS overexpression (OE) in NALM6-GL cancer cells attenuated CAR-T cells mediated cancer cell lysis. Asparaginase (ASPG) is an approved drug that breaks down circulating asparagine in leukemia cells, thereby depriving cancer cells of asparagine and inhibiting cancer growth. We proposed a hypothesis that ASPG engineered CAR-T cells undergo phenotype switching to overcome immunotherapy resistance in ALL. Coculture killing assay showed ASPG-OE CAR-T cells exhibited increased killing efficacy against ASNS - OE cancer cells by enhancing expression of granzyme B, IFN-γ, and TNF-α, whereas ASPG-KO CAR-T cells showed decreased cancer cells lysis efficiency. Phenotypic analysis revealed that ASPG-OE CAR-T cells exhibited distinct phenotypes, including increasing central memory T cells percentage, while decreasing effector memory T cells and effector memory cells that re-expressed CD45RA cells proportions. This distinct phenotype switch of ASPG - OE CAR-T cells toward central memory T cells exerted the increased killing efficacy against NALM6-GL cells even without ASNS-OE. The in vivo xenograft mouse model confirmed that ASPG-OE CAR-T cells exhibited superior anticancer activity against NALM6-GL cancer cells, while ASPG-KO CAR-T cells exhibited inferior anticancer activity. Taken together, ASPG orchestrates CAR-T cell distinct phenotype toward central memory T cells and reprogramming of asparagine metabolism for the enhancing antitumor immunity.

DOI: https://doi.org/10.1016/j.ymthe.2025.08.019
Clin Nutr. 2025 Jul 26. pii: S0261-5614(25)00194-3. [Epub ahead of print]52 195-202

Cytokine response to critical illness and its relation to amino acid metabolism.

Mette M Berger, Pierre Singer, Raven A Wierzchowska-McNew, Marina V Viana, Itai A Ben-David, Olivier Pantet, Caroline Perez, John J Thaden, Mariëlle P K J Engelen, Nicolaas E P Deutz.

   BACKGROUND AND AIMS: Critical illness is characterized by an intense inflammatory response that triggers major metabolic changes with protein catabolism resulting in major losses of muscle mass. The intensity of the inflammatory response appears as the principal driver of the changes involved in outcome, and especially those affecting protein metabolism and muscle catabolism, and resistance to nutrition. The present exploratory study aims to clarify the role of the different cytokines in amino acid metabolism.
METHODS: In this post-hoc analysis of the previously published observational study, including 51 critically ill patients and 49 healthy controls aiming at identifying patient changes in amino acid metabolism, we assessed the association between a panel of cytokines and blood levels of amino acids (AA) and their turnover. The subjects were matched for age, sex, and BMI. The study was conducted in postabsorptive state. Blood analysis included cytokines (determined by Luminex), C-reactive protein (CRP or hsCRP), and AA.
PROTOCOL: 8 mL solution containing 18 stable AA tracers administered as a pulse to calculate amino acid whole body production (WBP). WBP was calculated from fitted decay curves. We measured amino acid enrichments and concentrations by LC-MS/MS and derived statistics using Generalized Linear Model (GLM) t and stepwise regression. Data as means [95%CI].
RESULTS: The study included 51 critically ill patients (age 63 yrs [58, 68], APACHEII 21.6 [20, 24]) and 49 matched healthy controls (age 57 yrs [52, 61]). While anthropometric characteristics were similar between critically ill patients and healthy adults, phase angle was lower (3.9 [3.5, 4.2] vs 6.0 [5.6, 6.3], p < 0.001), most AA blood levels were lower, while most cytokine levels were significantly higher. IL-6 and CRP were strongly associated (p < 0.001). IL-6 was the cytokine with the strongest association with the AA blood levels and WBP alterations in patients. Three patterns of changes in the plasma cytokine concentrations were observed. Of the 37 cytokines measured, 12 were higher in ICU patients, 5 were lower, and the rest were similar.
CONCLUSIONS: The present study shows a comprehensive picture of inflammation and simultaneous alterations of AA metabolism. The levels of IL-6 and CRP may become a good indicator of the metabolic capacity to respond positively to nutrition therapy.
CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).

Keywords:  Amino acids; Critically ill; Cytokines; IL-6; Inflammation; Stable isotopes

DOI:  https://doi.org/10.1016/j.clnu.2025.07.018