bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–01–19
eleven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Autophagy related 7 (ATG7) regulates food intake and liver health during asparaginase exposure.
  2. Growth differentiation factor 15 is a glucose-downregulated gene acting as the crosstalk between stroma and cancer cells of the human bladder.
  3. GDF15 inhibits early-stage adipocyte differentiation by enhancing HOP2 expression and suppressing C/EBPα expression.
  4. Reductive stress-a common metabolic feature of obesity and cancer.
  5. IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.
  6. Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer.
  7. Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.
  8. PAR2 promotes malignancy in lung adenocarcinoma.
  9. High glucose induces pro-inflammatory polarization of macrophages by inhibiting immune-responsive gene 1 expression.
  10. Liver-Secreted Extracellular Vesicles Promote Cirrhosis-Associated Skeletal Muscle Injury Through mtDNA-cGAS/STING Axis.
  11. Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body.
  1. J Biol Chem. 2025 Jan 09. pii: S0021-9258(25)00018-3. [Epub ahead of print] 108171
    Autophagy related 7 (ATG7) regulates food intake and liver health during asparaginase exposure.
    Brian A Zalma, Maria Ibrahim, Flavio C Rodriguez-Polanco, Chintan T Bhavsar, Esther M Rodriguez, Eduardo Cararo-Lopes, Saad A Farooq, Jordan L Levy, Ronald C Wek, Eileen White, Tracy G Anthony.
      Amino acid starvation by the chemotherapy agent asparaginase is a potent activator of the integrated stress response (ISR) in liver and can upregulate autophagy in some cell types. We hypothesized that autophagy related 7 (ATG7), a protein that is essential for autophagy and an ISR target gene, was necessary during exposure to asparaginase to maintain liver health. We knocked down Atg7 systemically (Atg7Δ/Δ) or in hepatocytes only (ls-Atg7KO) in mice before exposure to pegylated asparaginase for 5 d. Intact mice injected with asparaginase lost body weight due to reduced food intake and increased energy expenditure. Systemic Atg7 ablation reduced liver protein synthesis and increased liver injury in vehicle-injected mice, but did not further reduce liver protein synthesis, exacerbate steatosis or liver injury, or alter energy expenditure following 5 d asparaginase exposure. Atg7Δ/Δ mice were unexpectantly protected from asparaginase-induced anorexia and weight loss. This protection corresponded with reduced phosphorylation of hepatic GCN2 and blunted increases in ISR gene targets including growth differentiation factor 15 (GDF15), a negative regulator of food intake. Interestingly, asparaginase elevated serum GDF15 and reduced food intake in ls-Atg7KO mice, similar to intact mice. Liver triglycerides and production of the hepatokine fibroblast growth factor 21, another ISR gene target, were suppressed in asparaginase-exposed Atg7Δ/Δ and ls-Atg7KO mice. This work identifies a bidirectional relationship between autophagy and the ISR in the liver during asparaginase, affecting food intake and liver health.
    Keywords:  FGF21; GDF15; amino acid; body composition; eukaryotic initiation factor 2 (eIF2); gene expression; polysome profiling; protein synthesis; translation
    DOI:  https://doi.org/10.1016/j.jbc.2025.108171
  2. Am J Physiol Cell Physiol. 2025 Jan 13.
    Growth differentiation factor 15 is a glucose-downregulated gene acting as the crosstalk between stroma and cancer cells of the human bladder.
    Kang-Shuo Chang, Syue-Ting Chen, Wei-Yin Lin, Shu-Yuan Hsu, Hsin-Ching Sung, Yu-Hsiang Lin, Tsui-Hsia Feng, Chen-Pang Hou, Horng-Heng Juang.
      Hyperglycemia and hyperglycosuria, two primary characteristics of diabetes mellitus, may increase the risk of cancer initiation, particularly for bladder cancer. The effectiveness of metformin, a common antidiabetic agent, is determined by its ability to induce GDF15. However, the mechanism of the GDF15 in relation to glucose, which influences the tumor microenvironment in the human bladder, is not fully understood. This study explores the potential roles of GDF15 in response to glucose in the human bladder. High glucose treatment (30 mM) enhanced phosphorylation of AKT at S473 and AMPK1/2 at S485 to block the counteracting effect of metformin on the AMPK activity in bladder cancer and stroma (HBdSF and HBdSMC) cells compared to normal glucose treatment (5 mM). Metformin modulated the expressions of GDF15, NDRG1, Maspin, and EMT markers to attenuate cell proliferation and invasion of bladder cancer cells. CAPE, like metformin, behaves as an inducer of AMPK activity to stimulate GDF15 expression. Knockdown of GDF15 blocked the downregulation of CAPE on the contraction of HBdSMC cells. Both CAPE-induced GDF15 expression and the supernatant from bladder cancer cells with overexpressing GDF15 impeded the HBdSF and HBdSMC cell migration, suggesting that CAPE-upregulated GDF15 blocked the cell migration. These findings reveal that high glucose treatment inhibits the counteracting effects of either metformin or CAPE on the AMPK activity, and GDF15 is downregulated by glucose and induced by metformin and CAPE in both stroma and cancer cells. Furthermore, GDF15 is an antitumor gene facilitating communication between stroma and cancer cells in the human bladder.
    Keywords:  AMPK; CAPE; GDF15; Stroma; bladder
    DOI:  https://doi.org/10.1152/ajpcell.00230.2024
  3. Mol Cell Endocrinol. 2025 Jan 13. pii: S0303-7207(25)00012-7. [Epub ahead of print] 112461
    GDF15 inhibits early-stage adipocyte differentiation by enhancing HOP2 expression and suppressing C/EBPα expression.
    Haeng Jun Kim, Sung-Un Kang, Hyo Jeong Kim, Yun Sang Lee, Chul-Ho Kim.
      Excessive adipocyte differentiation and accumulation contribute to the development of metabolic disorders. Growth differentiation factor 15 (GDF15) plays an essential role in energy homeostasis and is considered an anti-obesity factor; however, elevated serum levels of endogenous GDF15 have been reported in certain individuals with obesity. In this study, to gain a better understanding of this complex relationship between GDF15 levels and obesity, we investigated GDF15 expression and function during adipogenesis. Compared with mice fed a normal diet, those fed a short-term high-fat diet exhibited a reduction in epididymal white adipose tissue and serum GDF15 expression. These results were confirmed in human adipose-derived stem cells that showed reduced GDF15 expression during adipogenesis differentiation. During adipogenesis, GDF15 was primarily degraded via the autophagy lysosomal pathway, and GDF15 overexpression in pre-adipocytes inhibited adipogenesis by suppressing CCAAT enhancer binding protein alpha (C/EBPα). Furthermore, whereas we detected a reduction in homologous-pairing protein 2 (HOP2) expression during adipogenesis, expression increased in response to an overexpression of GDF15. Furthermore, following knockdown of HOP2 during GDF15 overexpression, there was no suppression of C/EBPα expression. These findings indicate that GDF15 undergoes lysosomal degradation via an autophagic pathway and suppresses adipocyte differentiation via the HOP2-mediated inhibition of C/EBPα expression. Collectively, our findings indicate that GDF15 could serve as a potential therapeutic target for the treatment of metabolic disorders.
    Keywords:  C/EBPα; GDF15; HOP2; adipocyte differentiation; adipogenesis
    DOI:  https://doi.org/10.1016/j.mce.2025.112461
  4. Acta Pharm Sin B. 2024 Dec;14(12): 5181-5185
    Reductive stress-a common metabolic feature of obesity and cancer.
    Man Luo, Xiwen Ma, Jianping Ye.
      Reductive stress, characterized by rising level of NADH (nicotinamide adenine dinucleotide) for a status of NADH/NAD+ ratio elevation, has been reported in obesity and cancer. However, the mechanism and significance of reductive stress remain to be established in obesity. This perspective is prepared to address the issue with new insights published recently. NADH is used in production of NADPH, glutathione, ATP and heat in the classical biochemistry. In obesity, elevation of NADH/NAD+ ratio, likely from overproduction due to substrate overloading, has been found in the liver for insulin resistance and gluconeogenesis. New evidence demonstrates that the elevation may induce lipogenesis, purine biosynthesis and gluconeogenesis through activation of transcription factors of ChREBP and NRF2. In cancer cells, NADH/NAD+ elevation under the Warburg effect is primarily derived from decreased NADH consumption in the mitochondrial respiration. Alternatively, NRF2 overactivation from gene mutation represents another mechanism of NADH/NAD+ elevation from NADH production in the cancer cells. The elevation is required for quick proliferation of cancer cells through induction of biosynthesis of the essential molecules. It appears that the causes of reductive stress are different between obesity and cancer, while its impact in anabolism is similar in the two conditions.
    Keywords:  Cancer; Gluconeogenesis; Lipogenesis; NADH; Obesity; Reductive stress
    DOI:  https://doi.org/10.1016/j.apsb.2024.08.034
  5. Cell Rep. 2025 Jan 11. pii: S2211-1247(24)01550-X. [Epub ahead of print]44(1): 115199
    IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.
    Seema Bachoo, Nancy Gudgeon, Rebecca Mann, Victoria Stavrou, Emma L Bishop, Audrey Kelly, Alejandro Huerta Uribe, Jordan Loeliger, Corina Frick, Oliver D K Maddocks, Paul Lavender, Christoph Hess, Sarah Dimeloe.
      Interleukin (IL)-7 promotes T cell expansion during lymphopenia. We studied the metabolic basis in CD4+ T cells, observing increased glucose usage for nucleotide synthesis and oxidation in the tricarboxylic acid (TCA) cycle. Unlike other TCA metabolites, glucose-derived citrate does not accumulate upon IL-7 exposure, indicating diversion into other processes. In agreement, IL-7 promotes glucose-dependent histone acetylation and chromatin accessibility, notable at the loci of the amino acid-sensing Ragulator complex. Consistently, the expression of its subunit late endosomal/lysosomal adaptor, MAPK and mTOR activator 5 (LAMTOR5) is promoted by IL-7 in a glucose-dependent manner, and glucose availability determines amino acid-dependent mechanistic target of rapamycin (mTOR) activation, confirming integrated nutrient sensing. LAMTOR5 deletion impairs IL-7-mediated T cell expansion, establishing that glycolysis in the absence of Ragulator activation is insufficient to support this. Clinically, CD4+ T cells from stem cell transplant recipients demonstrate coordinated upregulation of glycolytic and TCA cycle enzymes, amino acid-sensing machinery, and mTOR targets, highlighting the potential to therapeutically target this pathway to fine-tune lymphopenia-induced T cell proliferation.
    Keywords:  IL-7; Immunology; Metabolism; T cell; T lymphocyte; mTOR; metabolism; nutrient sensing; proliferation
    DOI:  https://doi.org/10.1016/j.celrep.2024.115199
  6. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13668
    Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer.
    Daria Neyroud, Andrew C D'Lugos, Enrique J Trevino, Chandler S Callaway, Jacqueline Lamm, Orlando Laitano, Brittney Poole, Michael R Deyhle, Justina Brantley, Lam Le, Andrew R Judge, Sarah M Judge.
       BACKGROUND: Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia.
    METHODS: To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild-moderate cachexia (D12 and D14) and advanced cachexia (endpoint).
    RESULTS: During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8-endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ+ fibroadipogenic progenitors (+2.5 to +3.8-fold; D10-endpoint vs. Sham, p < 0.05), fibre atrophy (-16% to -24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8-fold; D14-endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (-55%, p = 0.0074) and diaphragm excursion (-43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation.
    CONCLUSIONS: In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.
    Keywords:  cancer cachexia; inflammatory response; muscle atrophy; muscle fibrosis; pancreatic cancer
    DOI:  https://doi.org/10.1002/jcsm.13668
  7. Cell Metab. 2025 Jan 03. pii: S1550-4131(24)00480-7. [Epub ahead of print]
    Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.
    Yizeng Fan, Weichao Dan, Yuzhao Wang, Zhiqiang Ma, Yanlin Jian, Tianjie Liu, Mengxing Li, Zixi Wang, Yi Wei, Bo Liu, Peng Ding, Yuzeshi Lei, Chendong Guo, Jin Zeng, Xiaolong Yan, Wenyi Wei, Lei Li.
      Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.
    Keywords:  IRG1; PD-L1; SLC13A3; immunotherapy; itaconate
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.012
  8. Am J Transl Res. 2024 ;16(12): 7416-7426
    PAR2 promotes malignancy in lung adenocarcinoma.
    Bao Wang, Ming-Da Wu, Yue-Jiao Lan, Chun-Yi Jia, Hui Zhao, Kun-Peng Yang, Hao-Nan Liu, Shi-Zhuo Sun, Ran-Cen Tao, Xiao-Dan Lu, Zhen-Fa Zhang.
      Proteinase-activated receptor-2 (PAR2) is closely linked to tumor malignancy, but its biological role in cancer remains underexplored. In this study, we assessed PAR2 expression in lung adenocarcinoma (LUAD) and normal lung tissues, analyzed associations between clinicopathological features and survival rates, and confirmed that PAR2 promotes apoptosis resistance and reduces cisplatin-induced cytotoxicity in lung cancer cells. Using TCGA datasets, western blotting, qPCR, and immunohistochemistry (IHC), we observed a significant increase in PAR2 levels in LUAD samples compared to normal tissues (P<0.05), with high PAR2 expression correlating with poor differentiation and lymphatic invasion (P<0.05). Upregulated PAR2 was associated with reduced survival. Additionally, PAR2 inhibition increased the BAX/BCL-2 axis and contributed to cisplatin-induced endoplasmic reticulum stress and apoptosis in H1299 cells. However, PAR2 inhibition reduced cisplatin-induced ATF4 expression. Overall, PAR2 upregulation is strongly associated with poor postoperative survival, differentiation, and lymphatic metastasis in LUAD and modulates cisplatin cytotoxicity.
    Keywords:  Lung cancer; PAR2; cisplatin; lymphatic metastasis; survival
    DOI:  https://doi.org/10.62347/STSI5751
  9. Nan Fang Yi Ke Da Xue Xue Bao. 2025 Jan 20. pii: 1673-4254(2025)01-0001-09. [Epub ahead of print]45(1): 1-9
    High glucose induces pro-inflammatory polarization of macrophages by inhibiting immune-responsive gene 1 expression.
    Wei Luo, Yuhang Wang, Yansong Liu, Yuanyuan Wang, Lei Ai.
       OBJECTIVES: To investigate the effect of high glucose on macrophage polarization and the role of immune-responsive gene 1 (IRG1) in mediating its effect.
    METHODS: RAW264.7 cells were transfected with IRG1-overexpressing plasmid or IRG1 siRNA via electroporation and cultured in either normal or high glucose for 72 h to observe the changes in cell viability and morphology using CCK-8 assay and phase contrast microscopy. The protein levels of IRG1, iNOS, Arg-1, IL-1β and IL-10 in the treated cells were detected with Western blotting, and the fluorescence intensities of iNOS and Arg-1 were detected using immunofluorescence assay. The protein levels of IL-1β and IL-10 in the culture medium were determined with ELISA.
    RESULTS: High glucose exposure significantly reduced IRG1 and Arg-1 expressions, increased iNOS and IL-1β expressions and IL-1β secretion, and decreased IL-10 level in RAW264.7 cells. Transfection with the IRG1-overexpressing plasmid provided the cells with obvious resistance to high glucose-induced changes in iNOS, Arg-1, IL-1β and IL-10, whereas IRG1 knockdown further enhanced the effects of high glucose exposure on Arg-1 expression and the expression and secretion of IL-10.
    CONCLUSIONS: High glucose promotes M1 polarization of the macrophages possibly through a mechanism to inhibit the expression of IRG1 protein, thus leading to chronic inflammatory response.
    Keywords:  M1 polarization; high glucose condition; immune-responsive gene 1; inflammatory cytokines; macrophages
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.01.01
  10. Adv Sci (Weinh). 2025 Jan 13. e2410439
    Liver-Secreted Extracellular Vesicles Promote Cirrhosis-Associated Skeletal Muscle Injury Through mtDNA-cGAS/STING Axis.
    Xiaoli Fan, Yunke Peng, Bo Li, Xiaoze Wang, Yifeng Liu, Yi Shen, Guofeng Liu, Yanyi Zheng, Qiaoyu Deng, Jingping Liu, Li Yang.
      Skeletal muscle atrophy (sarcopenia) is a serious complication of liver cirrhosis, and chronic muscle inflammation plays a pivotal role in its pathologenesis. However, the detailed mechanism through which injured liver tissues mediate skeletal muscle inflammatory injury remains elusive. Here, it is reported that injured hepatocytes might secrete mtDNA-enriched extracellular vesicles (EVs) to trigger skeletal muscle inflammation by activating the cGAS-STING pathway. Briefly, injured liver secreted increased amounts of EVs into circulation, which are then engulfed primarily by macrophages in skeletal muscle and subsequently induce cGAS-STING signaling and its-mediated inflammatory response in muscles. In contrast, suppression of hepatic EV secretion or STING signaling significantly alleviated cirrhosis-induced skeletal muscle inflammation and muscle atrophy in vivo. Circulating EVs from cirrhotic patients showed higher levels of mtDNA, and the levels of EV-mtDNA positively correlated with the severity of liver injury. In injured hepatocytes, mitochondrial damage promoted the release of cytosolic mtDNA and the subsequent secretion of mtDNA-enriched EVs. This study reveals that injured hepatocyte-derived EVs induce skeletal muscle inflammation via the mtDNA‒STING axis, while targeted blockade of liver EV secretion or STING signaling represents a potential therapeutic approach for preventing cirrhosis-associated skeletal muscle atrophy.
    Keywords:  cGAS‐STING; extracellular vesicles; liver fibrosis; mtDNA; skeletal muscle atrophy
    DOI:  https://doi.org/10.1002/advs.202410439
  11. Mol Metab. 2025 Jan 08. pii: S2212-8778(25)00002-X. [Epub ahead of print]92 102095
    Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body.
    Luis Leon-Mercado, Ivan Menendez-Montes, Jonathan Tao, Bandy Chen, David P Olson, C Mackaaij, C G J Cleypool, Laurent Gautron.
      Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized in oxygen sensing, we proceeded to investigate whether Agrp expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. In vitro luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our in vivo experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces Agrp expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of Agrp transcription by HIF signaling.
    Keywords:  Cardiovascular adaptation; Hypoxia; Melanocortins; Neuropeptide; Transcription
    DOI:  https://doi.org/10.1016/j.molmet.2025.102095
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