bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–02–23
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. SIRT6 Ameliorates Cancer Cachexia-Associated Adipose Wasting by Suppressing TNFR2 Signalling in Mice.
  2. Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential.
  3. The integrated stress response engages a cell-autonomous, ligand-independent, DR5-driven apoptosis switch.
  4. Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
  5. Complement activation at the interface between adipocytes and cancer cells drives tumor progression.
  6. Transcriptomic analysis of human primary T cells after short-term leucine-deprivation and evaluation of kinase GCN2's role in regulating differential gene expression.
  7. One-carbon metabolism is distinct metabolic signature for proliferative intermediate exhausted T cells of ICB-resistant cancer patients.
  8. Growth Differentiation Factor-15 Predicts Major Bleeding in Cancer Patients: Results From the Vienna CAT-BLED Study.
  9. Metabolic and stress response adaptations in T cells to fever and physiological heat.
  1. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13734
    SIRT6 Ameliorates Cancer Cachexia-Associated Adipose Wasting by Suppressing TNFR2 Signalling in Mice.
    Kang Xu, Yida Wang, Fang Wang, Yannan Guo, Yu Ren, Vivien Low, Sungyun Cho, Qingfei Liu, Ying Qiu, Xue Li, Kang Yu, Zhongchi Li, Zhao Wang.
       BACKGROUND: Cachexia is a wasting syndrome associated with imbalanced energy metabolism and loss of adipose and muscle tissues and contributes to morbidity and mortality in ageing as well as in patients with severe chronic diseases, including cancer. At present, there are no treatments addressing cachexia that have reached validation to be used in the clinic. In this study, we investigate the protective role of SIRT6, an important regulator of energy homeostasis and health preservation, against Lewis lung carcinoma (LLC)-induced cachexia.
    METHODS: SIRT6 levels of serum from gastric cancer patients (n = 22, 65.27 ± 12.50 years old, 40.9% females) and healthy controls (n = 22, 63.50 ± 10.77 years old, 45.4% females) were measured to evaluate the correlation between circulating SIRT6 levels and cancer cachexia development. Ten-week-old SIRT6 transgenic (TG) and wild type (WT) male mice injected with LLC cells (1.5 × 106 per mouse) were used to investigate the protective effects of SIRT6 on cachexia-associated adipose browning and lipolysis and the underlying mechanisms. We explored the effect of SIRT6 on LLC-conditioned medium induced lipolysis in mature adipocytes, differentiated from primary mouse embryonic fibroblasts (MEFs). We evaluated the in vitro effect of a SIRT6 activator by treatment of MDL800.
    RESULTS: SIRT6 concentrations were significantly higher in non-cachectic cancer patients (3.41 ± 0.30 ng/mL) compared to cachectic cancer patients (3.20 ± 0.23 ng/mL, p < 0.01), suggesting the negative correlation between SIRT6 level and cachexia in patients with cancer. SIRT6 overexpression significantly ameliorated tumour-induced wasting and energy expenditure in white adipose tissues (eWAT mass loss: 66% in WT vs. 32% in TG; iWAT mass loss: 69% in WT vs. 40% in TG) through suppression of browning and lipolysis. In LLC-induced cachexia, tumour necrosis factor-α receptor 2 (TNFR2) mediated the inhibition of SIRT6 on lipolytic signalling, because the difference in lipolysis between the WT and SIRT6 knockout group was almost eliminated by TNFR2 neutralizing antibody. Increased serum TNFR2 concentration was found in cachectic cancer patients (690.41 pg/mL in non-cachectic vs. 1166.98 pg/mL in cachectic patients, p < 0.05). A selective SIRT6 pharmaceutical activator, MDL800, could completely reverse LLC-induced lipolysis in adipocytes.
    CONCLUSION: We found an unexpected beneficial function of SIRT6 in cancer cachexia, demonstrating that increased SIRT6 expression or activity is capable of protecting the host against cachexia-associated tissue wasting, providing a concept of future therapies for cachexia.
    Keywords:  SIRT6; SIRT6 activator; TNFR2 antagonist; adipose wasting; cachexia
    DOI:  https://doi.org/10.1002/jcsm.13734
  2. Semin Cancer Biol. 2025 Feb 13. pii: S1044-579X(25)00013-6. [Epub ahead of print]110 65-82
    Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential.
    Zhixue Chen, Lin Xu, Yejv Yuan, Si Zhang, Ruyi Xue.
      Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.
    Keywords:  Cancer therapy; Energy metabolism; Mitochondrial transfer; Platelet
    DOI:  https://doi.org/10.1016/j.semcancer.2025.02.001
  3. Cell Death Dis. 2025 Feb 15. 16(1): 101
    The integrated stress response engages a cell-autonomous, ligand-independent, DR5-driven apoptosis switch.
    Francesca Zappa, Nerea L Muniozguren, Julia E Conrad, Diego Acosta-Alvear.
      The integrated stress response (ISR) is a fundamental signaling network that leverages the cell's biosynthetic capacity against different stresses to restore homeostasis. However, when homeostasis is unattainable, the ISR switches to drive cell death and eliminate irreparably damaged cells. Previous work has shown that persistent activity of the ISR kinase PERK during unyielding endoplasmic reticulum (ER) stress induces apoptosis downstream of death receptor 5 (DR5) [1]. ER stress provides activating signals that engage the ectodomain (ED) of DR5 to drive its unconventional activation in the Golgi apparatus [1, 2]. Here, using chemical genetics to uncouple stress sensing from ISR activation, we found that DR5 signaling from the Golgi apparatus is integral to the ISR and not specific to ER stress. Furthermore, we show that DR5 activation can be driven solely by increased expression and does not require its ED. These findings indicate that a general ISR kill switch eliminates irreversibly injured cells.
    DOI:  https://doi.org/10.1038/s41419-025-07403-8
  4. bioRxiv. 2025 Jan 31. pii: 2025.01.28.635306. [Epub ahead of print]
    Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
    Caroline Trumpff, Qiuhan Huang, Jeremy Michelson, Cynthia C Liu, David Shire, Christian G Habeck, Yaakov Stern, Martin Picard.
      Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1) cell-free mitochondrial DNA (cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2) growth differentiation factor 15 (GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.
    DOI:  https://doi.org/10.1101/2025.01.28.635306
  5. JCI Insight. 2025 Feb 18. pii: e184935. [Epub ahead of print]
    Complement activation at the interface between adipocytes and cancer cells drives tumor progression.
    Andres Valdivia, Ana Isac, Horacio Cardenas, Guangyuan Zhao, Yaqi Zhang, Hao Huang, Jian-Jun Wei, Mauricio Cuello-Fredes, Sumie Kato, Fernán Gómez-Valenzuela, Francoise A Gourronc, Aloysius J Klingelhutz, Daniela Matei.
      The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and pro-metastatic phenotype. Here we studied cancer cell-adipocyte crosstalk by using a direct co-culture model with immortalized human visceral pre-adipocytes (VNPAD) and OC cells. We demonstrate increased proliferation, invasiveness, and resistance to cisplatin of co-cultured compared to mono-cultured OC cells. RNA-sequencing of OC cells from co-culture vs. mono-culture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes (DEGs) common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/AKT and Complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in-vivo. Increased C3 expression was observed in omental implants compared to primary ovarian tumors and C3 secretion was higher in OC ascites from high BMI vs. low BMI patients. C3 upregulation in OC cells involved activation of ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promote invasiveness and tumorigenesis via lipid transfer, activating ISR, and upregulating complement proteins C3 and C5.
    Keywords:  Adipose tissue; Cancer; Cell biology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.184935
  6. PLoS One. 2025 ;20(2): e0317505
    Transcriptomic analysis of human primary T cells after short-term leucine-deprivation and evaluation of kinase GCN2's role in regulating differential gene expression.
    Aurore Dougé, Gwendal Cueff, Céline Keime, Valérie Carraro, Céline Jousse, Paul Rouzaire, Alain Bruhat.
      Chimeric Antigen Receptor T (CAR-T) cells offer a promising strategy for cancer treatment. These CAR-T cells are either autologous or allogeneic T cells that are genetically modified to express a chimeric antigen receptor targeting a specific tumor antigen. Ongoing research aims to optimize the CAR-T cell efficacy, including strategies to modulate their metabolism. One such approach involves inducing transgene expression by activating the GCN2 kinase signaling pathway through dietary deprivation of an essential amino acid. In this study, we investigated the general impact of a 6-hour leucine deprivation on primary activated human T cells using RNA-seq technology. Our analysis identified 3,431 differentially expressed genes between T cells cultured in regular medium and those cultured in leucine-deprived medium. Gene Set Enrichment Analysis revealed that "TNFα signaling via NFκB", "interferon-γ response", and "unfolded protein response" gene sets were positively enriched, while "mTORC1 signaling", "Myc targets", and "oxidative phosphorylation" gene sets were negatively enriched. To further evaluate the involvement of GCN2 kinase in regulating the differential gene expression during the 6-hour leucine deprivation, T cells were cultured with or without a GCN2 inhibitor. We found that 59% of the differentially expressed genes in our dataset were dependent on the kinase GCN2 (n = 2028), with 1,140 up-regulated and 888 down-regulated genes. These findings suggest a promising strategy to enhance CAR-T cell efficacy by combining short amino acid starvation with transient overexpression of a target gene.
    DOI:  https://doi.org/10.1371/journal.pone.0317505
  7. Cell Death Discov. 2025 Feb 14. 11(1): 60
    One-carbon metabolism is distinct metabolic signature for proliferative intermediate exhausted T cells of ICB-resistant cancer patients.
    Ye-Chan Park, Yeseong Hwang, Jae Woong Jeong, Chae Min Lee, Minki Kim, Sugyeong Jo, Seyeon Joo, Nahee Hwang, Sungsoon Fang.
      One-carbon metabolism (1CM) has been reported to promote cancer progression across various malignancies. While 1CM is critical for cell proliferation by enhancing nucleotide synthesis, its physiological roles within different cell types in the tumor immune microenvironment (TIME) still remain unclear. In this study, we analyzed bulk-RNA sequencing and single-cell RNA sequencing (scRNA-seq) data from lung adenocarcinoma (LUAD) patients to elucidate the functional roles of 1CM within the TIME. Moreover, we examined scRNA-seq data from patients treated with immunotherapy across various cancers, including LUAD, glioblastoma, renal cell carcinoma, colorectal cancer, and triple-negative breast cancer. Compared to other cell types, 1CM gene profiles are significantly enriched in a specific subset of T cells. Intriguingly, these high-1CM T cells are identified as proliferative intermediate exhausted T cells (Texint). Furthermore, these proliferative Texint received the most robust CD137 signaling. Consistently, analysis of scRNA-seq data from LUAD patients undergoing anti-PD1 immunotherapy demonstrated that proliferative Texint exhibited higher 1CM scores and increased CD137 signaling. This observation was particularly pronounced in non-responders to immunotherapy, where the Texint population was significantly expanded. We further established that 1CM is a prominent signaling pathway in proliferative Texint in patients resistant to immunotherapy across multiple cancer types. Collectively, we identify CD137 signaling as a distinctive pathway in proliferative Texint of LUAD patients who do not respond to immunotherapy. These findings propose that targeting 1CM may represent a novel therapeutic strategy to enhance the efficacy of immunotherapy by mitigating Texint proliferation in diverse cancers.
    DOI:  https://doi.org/10.1038/s41420-025-02332-z
  8. JACC CardioOncol. 2025 Feb;pii: S2666-0873(24)00424-1. [Epub ahead of print]7(2): 141-152
    Growth Differentiation Factor-15 Predicts Major Bleeding in Cancer Patients: Results From the Vienna CAT-BLED Study.
    Cornelia Englisch, Stephan Nopp, Florian Moik, Daniel Steiner, Angelika M Starzer, Monika Fritzer-Szekeres, Matthias Preusser, Anna S Berghoff, Ingrid Pabinger, Cihan Ay.
       BACKGROUND: The hemostatic system is tightly interconnected with cancer. Research has focused predominantly on thrombotic complications, but less is known about bleeding and bleeding risk prediction. Growth differentiation factor (GDF)-15 has previously emerged as a prognostic biomarker for bleeding.
    OBJECTIVES: The aim of this study was to investigate the association and predictive ability of GDF-15 for bleeding risk in patients with cancer.
    METHODS: The CAT-BLED (Vienna Cancer, Thrombosis, and Bleeding) study is a prospective, observational cohort study including cancer patients initiating systemic anticancer therapies. Patients were followed for up to 2 years for thrombotic and bleeding events. The primary outcome was major bleeding. GDF-15 was measured at inclusion and at 3 and 6 months of follow-up.
    RESULTS: A total of 779 patients (48% women, median age 62 years, 15% on therapeutic anticoagulation) were included. During a median follow-up period of 18 months, 79 patients (10.1%) experienced major bleeding (12-month cumulative incidence 8.8%; 95% CI: 6.7-10.9). Higher GDF-15 levels were independently associated with increased major bleeding risk (adjusted subdistribution HR per doubling: 1.29; 95% CI: 1.04-1.59), and patients with levels greater than the cohort median (1,864 ng/L) had a significantly higher 12-month cumulative incidence (13.1% vs 4.6%; P < 0.001). This association remained robust in follow-up measurements at 3 and 6 months. GDF-15 showed moderate to good discrimination for predicting 6-month major bleeding risk (C statistic = 0.69; 95% CI: 0.60-0.77). GDF-15 was not associated with venous thromboembolism but was strongly associated with mortality (adjusted HR: 1.37; 95% CI: 1.25-1.50).
    CONCLUSIONS: GDF-15 levels predict major bleeding risk in cancer patients and are not associated with venous thromboembolism, making GDF-15 a particularly promising biomarker for bleeding risk prediction.
    Keywords:  biomarkers; bleeding; cancer; hemorrhage; major bleeding; risk prediction
    DOI:  https://doi.org/10.1016/j.jaccao.2024.11.007
  9. Trends Immunol. 2025 Feb 20. pii: S1471-4906(25)00025-0. [Epub ahead of print]
    Metabolic and stress response adaptations in T cells to fever and physiological heat.
    Benjamin A Wilander, Jeffrey C Rathmell.
      Fevers are an ancient feature of the inflammatory microenvironment. While fevers may improve the immune response to pathogens, mechanisms are unclear. We explore recent studies of how fever-range temperatures inform mammalian T cell metabolism, differentiation, and stress responses. Recent evidence indicates that metabolic programs initiated by fever are maintained upon return to thermo-normality, potentially providing a lasting benefit. Despite its impact, temperature remains overlooked and warrants further study. This is especially apparent when considering the wide temperature differential between tissues within the body and during inflammatory disease progression. We propose that differences in the metabolic and stress responses between T cell subsets upon thermal stress contribute to determining immune cell makeup and fate during inflammation.
    Keywords:  T cells; fever; immunometabolism; stress
    DOI:  https://doi.org/10.1016/j.it.2025.01.007
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