bims-stacyt 2025-01-12 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–01–12
twelve papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

The integrated stress response drives MET oncogene overexpression in cancers.
Impact of Serum GDF-15 and IL-6 on Immunotherapy Response in Cancer: A Prospective Study.
D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint.
Exploring the mechanism and crosstalk between IL-6 and IL- 1β on M2 macrophages under metabolic stress conditions.
Selpercatinib mitigates cancer cachexia independent of anti-tumor activity in the HT1080 tumor model.
IGFBP2 Promotes Proliferation and Glycolysis of Endometrial Cancer by Regulating PKM2/HIF-1α Axis.
Systemic metabolic crosstalk as driver of cancer cachexia.
Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression.
GDF15 promotes corneal neovascularization and RB cell progression via AKT/ERK signal pathway.
The Tumor Metabolite 5'-Deoxy-5'Methylthioadenosine (MTA) Inhibits Maturation and T Cell-Stimulating Capacity of Dendritic Cells.
Exercise promotes peripheral glycolysis in skeletal muscle through miR-204 induction via the HIF-1α pathway.
Elevated Serum IL-6 as a Negative Prognostic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Validation.

EMBO J. 2025 Jan 07.

The integrated stress response drives MET oncogene overexpression in cancers.

Marina Cerqua, Marco Foiani, Carla Boccaccio, Paolo M Comoglio, Dogus M Altintas.

  Cancer cells rely on invasive growth to survive in a hostile microenvironment; this growth is characterised by interconnected processes such as epithelial-to-mesenchymal transition and migration. A master regulator of these events is the MET oncogene, which is overexpressed in the majority of cancers; however, since mutations in the MET oncogene are seen only rarely in cancers and are relatively infrequent, the mechanisms that cause this widespread MET overexpression remain obscure. Here, we show that the 5' untranslated region (5'UTR) of MET mRNA harbours two functional stress-responsive elements, conferring translational regulation by the integrated stress response (ISR), regulated by phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) at serine 52. ISR activation by serum starvation, leucine deprivation, hypoxia, irradiation, thapsigargin or gemcitabine is followed by MET protein overexpression. We mechanistically link MET translation to the ISR by (i) mutation of the two uORFs within the MET 5'UTR, (ii) CRISPR/Cas9-mediated mutation of eIF2α (S52A), or (iii) the application of ISR pathway inhibitors. All of these interventions reduce stress-induced MET overexpression. Finally, we show that blocking stress-induced MET translation blunts MET-dependent invasive growth. These findings indicate that upregulation of the MET oncogene is a functional requirement linking integrated stress response to cancer progression.

Keywords:  Integrated Stress Response; Invasive Growth; MET Oncogene

DOI:  https://doi.org/10.1038/s44318-024-00338-4
Cancers (Basel). 2024 Dec 12. pii: 4146. [Epub ahead of print]16(24):

Impact of Serum GDF-15 and IL-6 on Immunotherapy Response in Cancer: A Prospective Study.

Orhun Akdogan, Sena Turkmen, Galip Can Uyar, Kadriye Bir Yucel, Busra Tufekci, Fatih Gurler, Ozan Yazici, Nuriye Ozdemir, Ahmet Ozet, Cengiz Karakaya, Osman Sutcuoglu.

   BACKGROUND: Immunotherapy has transformed cancer treatment; however, predicting treatment response remains challenging. Serum biomarkers can help identify patients who are most likely to benefit from immunotherapy.
OBJECTIVE: This study evaluates the relationship between serum growth differentiation factor 15 (GDF-15) and interleukin-6 (IL-6) levels and treatment outcomes in cancer patients undergoing second-line immunotherapy.
METHODS: We conducted a prospective observational study involving 85 patients with non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), or malignant melanoma treated with nivolumab. The baseline serum levels of GDF-15 and IL-6 were measured by using ELISA kits. The primary endpoints were progression-free survival (PFS) and overall survival (OS), with cachexia as a secondary outcome.
RESULTS: Elevated GDF-15 levels were significantly associated with shorter PFS (HR: 0.55, 95% CI: 0.32-0.96, p = 0.032) and OS (HR: 0.47, 95% CI: 0.25-0.90, p = 0.020). Higher IL-6 levels correlated with shorter PFS, though statistical significance was not achieved. Additionally, high GDF-15 levels were linked to increased cachexia incidence (p = 0.037).
CONCLUSION: Our findings indicate that GDF-15 could serve as a prognostic biomarker for immunotherapy response and may also be a target for cachexia management. Further studies should explore its potential to guide clinical decision making in oncology.

Keywords:  Growth Differentiation Factor 15 (GDF-15); Interleukin-6 (IL-6); immunotherapy response

DOI:  https://doi.org/10.3390/cancers16244146
J Hematol Oncol. 2025 Jan 04. 18(1): 2

D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint.

Cheng-E Tu, Yong-Feng Liu, Hong-Wei Liu, Chun-Mei Jiao, Quentin Liu, Mien-Chie Hung, Peng Li, Xiang-Bo Wan, Xin-Juan Fan, Yun-Long Wang.

   BACKGROUND: Targeting glucose uptake by glucose transporter (GLUT) inhibitors is a therapeutic opportunity, but efforts on GLUT inhibitors have not been successful in the clinic and the underlying mechanism remains unclear. We aim to identify the key metabolic changes responsible for cancer cell survival from glucose limitation and elucidate its mechanism.
METHODS: The level of phosphorylated YAP was analyzed with Western blotting and Phos-tag immunoblotting. Glucose limitation-induced metabolic changes were analyzed using targeted metabolomics (600MRM). The anti-cancer role of metabolite was examined using colony formation assay and APCmin/+ mice. Co-immunoprecipitation, LS-MS, qRT-PCR, and immunofluorescence were performed to explore the underlying mechanisms.
RESULTS: We found that D-Ribose-5-phosphate (D5P), a product of the pentose phosphate pathway connecting glucose metabolism and nucleotide metabolism, functions as a metabolic checkpoint to activate YAP under glucose limitation to promote cancer cell survival. Mechanistically, in glucose-deprived cancer cells, D5P is decreased, which facilitates the interaction between MYH9 and LATS1, resulting in MYH9-mediated LATS1 aggregation, degradation, and further YAP activation. Interestingly, activated YAP further promotes purine nucleoside phosphorylase (PNP)-mediated breakdown of purine nucleoside to restore D5P in a feedback manner. Importantly, D5P synergistically enhances the tumor-suppressive effect of GLUT inhibitors and inhibits cancer progression in mice.
CONCLUSIONS: Our study identifies D5P as a metabolic checkpoint linking glucose limitation stress and YAP activation, indicating that D5P may be a potential anti-cancer metabolite by enhancing glucose limitation sensitivity.

Keywords:  D-ribose-5-phosphate; Glucose deprivation; LATS1; Metabolic stress; Purine nucleoside phosphorylase; YAP

DOI:  https://doi.org/10.1186/s13045-024-01655-1
Cytokine. 2025 Jan 06. pii: S1043-4666(24)00356-9. [Epub ahead of print]186 156852

Exploring the mechanism and crosstalk between IL-6 and IL- 1β on M2 macrophages under metabolic stress conditions.

Shawna Yadav, Anusha Prasannan, Kaliyamurthi Venkatachalam, Ambika Binesh.

  Macrophages are highly variable immune cells that are important in controlling inflammation and maintaining tissue balance. The ability to polarize into two major types-M1, promoting inflammation, and M2, resolving inflammation and contributing to tissue repair-determines their specific roles in health and disease. M2 macrophages are particularly important for reducing inflammation and promoting tissue regeneration, but their function is shaped mainly by surrounding cells. This is evident in obesity, diabetes, and chronic inflammation. Although many cytokines regulate macrophage polarization, interleukin-6 (IL-6) and interleukin-1β (IL-1β) are major players, but their effects on M2 macrophage behavior under metabolic stress remain unclear. This study describes the intricacies within M2 macrophages concerning IL-6 and IL-1β signaling when under metabolic stress. Though, more frequently than not, IL-6 is labelled as pro-inflammatory, it can also behave as an anti-inflammatory mediator. On the other hand, IL-1β is the main pro-inflammatory agent, particularly in metabolic disorders. The relationship between these cytokines and the macrophages is mediated through important pathways such as JAK/STAT and NFκB, which get perturbed by metabolic stress. Therefore, metabolic stress also alters the functional parameters of macrophages, including alterations in mitochondrial metabolism, glycolytic and oxidative metabolism. Phosphorylation alters the kinetics involved in energy consumption and affects their polarization and their function. However, it has been suggested that IL-6 and IL-1β may work in concert or competition when inducing M2 polarization and, importantly, implicate cytokine release, phagocytic activity, and tissue repair processes. In this review, we discuss the recent literature on the participation of IL-6 and IL-1β cytokines in macrophage polarization and how metabolic stress changes cytokine functions and synergistic relations. A better understanding of these cytokines would serve as an important step toward exploring alternative antiviral strategies directed against metabolic disturbance and, hence, approve further endeavors.

Keywords:  Interleukin-6; Interleulin-1β; Macrophage polarization and inflammation; Macrophages; Metabolic stress

DOI:  https://doi.org/10.1016/j.cyto.2024.156852
Cancer Lett. 2025 Jan 06. pii: S0304-3835(25)00008-4. [Epub ahead of print]611 217444

Selpercatinib mitigates cancer cachexia independent of anti-tumor activity in the HT1080 tumor model.

Ujjwol Khatri, Mohamed A Gouda, Shriya Pandey, Neeraj K Chauhan, Tao Shen, Xueqing Hu, Min Li, Suming Huang, Vivek Subbiah, Jie Wu.

  Anorexia is a major cause of cancer cachexia and is induced by growth differentiation factor-15 (GDF15), which activates the rearranged during transfection (RET) protein tyrosine kinase in the hindbrain through GDF family receptor α-like (GFRAL), raising the possibility of targeting RET for cancer cachexia treatment. RET-altered cancer patients treated with RET-selective kinase inhibitors gain weight, however, it is unclear whether this results from tumor regression that improves the overall health of patients. Thus, the potential of using a RET inhibitor to address cancer cachexia remains unknown. Using a RET-negative tumor model, we evaluated the activity of the RET-selective inhibitor selpercatinib (LOXO-292) against cancer cachexia. In tumor-bearing animals, selpercatinib significantly increased food consumption, skeletal muscle mass and strength, adipose tissues, and body temperature, as well as reducing body weight loss, without significantly affecting tumor growth. Transcriptomes of skeletal muscle from mock-treated tumor-bearing mice were enriched in starvation and muscle atrophy genes, whereas those from selpercatinib-treated mice were enriched in myoblast proliferation, gluconeogenesis, and insulin receptor signaling genes. In parallel, retrospective analysis of weight gain in selpercatinib-treated patients showed that weight gain was not correlated with tumor response to selpercatinib. Our data demonstrate that selpercatinib could alleviate anorexia and cancer cachexia in an animal model and that weight gain in selpercatinib-treated patients is not dependent on tumor regression. These results identify a RET inhibitor as the first protein tyrosine kinase inhibitor for mitigating cancer cachexia.

Keywords:  Anorexia; Cancer cachexia; Kinase inhibitor; Muscle atrophy; RET; Selpercatinib

DOI:  https://doi.org/10.1016/j.canlet.2025.217444
Cancer Sci. 2025 Jan 06.

IGFBP2 Promotes Proliferation and Glycolysis of Endometrial Cancer by Regulating PKM2/HIF-1α Axis.

Yuxi Jin, Meng Qi, Lulu Si, Xiaojing Shi, Mingbo Cai, Hanlin Fu, Yana Liu, Ruixia Guo.

  Endometrial cancer (EC) is a worldwide gynecologic malignancies, with a remarking increase of incidence and mortality rates in recent years. Growing evidence indicates that glucose metabolism reprogramming is the most representative metabolic signature of tumor cells and exploring its modulatory function in EC development will promote identifying potential EC therapeutic targets. IGFBP2 is an insulin-like growth factor binding protein which is closely associated with a variety of metabolic diseases. However, its biological role in EC and its effects on glucose metabolism remain unclear. In this study, we demonstrated that IGFBP2 was highly expressed in EC tissues and correlated with poor prognosis. Overexpression of IGFBP2 promoted proliferation and glycolysis in EC cells, whereas IGFBP2 knockdown had the opposite effect. Mechanistically, IGFBP2 directly interacted with PKM2, inducing weakened PKM2 protein degradation, and knockdown IGFBP2 expression prevented the translocation of PKM2 to the nucleus. Additionally, IGFBP2 expression was upregulated under the condition of hypoxia which directly regulated by transcriptional activation of HIF-1α. Finally, the role of the IGFBP2/PKM2/HIF-1α axis in EC tumor growth was confirmed in vivo using mouse xenograft models. Taken together, the current study identifies IGFBP2 as an upstream activator of PKM2-driven proliferation and glycolysis in EC cells, providing a promising therapeutic target for EC.

Keywords:  HIF‐1α; IGFBP2; PKM2; endometrial cancer; glycolysis

DOI:  https://doi.org/10.1111/cas.16447
Trends Endocrinol Metab. 2025 Jan 04. pii: S1043-2760(24)00327-8. [Epub ahead of print]

Systemic metabolic crosstalk as driver of cancer cachexia.

Elisabeth Wyart, Giovanna Carrà, Elia Angelino, Fabio Penna, Paolo E Porporato.

  Cachexia is a complex metabolic disorder characterized by negative energy balance due to increased consumption and lowered intake, leading to progressive tissue wasting and inefficient energy distribution. Once considered as passive bystander, metabolism is now acknowledged as a regulator of biological functions and disease progression. This shift in perspective mirrors the evolving understanding of cachexia itself, no longer viewed merely as a secondary consequence of cancer but as an active process. However, metabolic dysregulations in cachexia are currently studied in an organ-specific manner, failing to be fully integrated into a comprehensive framework that explains their functional roles in disease progression. Thus, in this review, we aim to provide a general overview of the various metabolic alterations with a potential systemic impact.

Keywords:  cachexia; cross-talk; metabolism; muscle wasting

DOI:  https://doi.org/10.1016/j.tem.2024.12.005
iScience. 2024 Dec 20. 27(12): 111502

Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression.

Kako Hanada, Yuki Saito, Takahiro Takagi, Mitsuki Go, Yota Nakano, Toshihiko Inagawa, Hideyo Hirai, Marcus Fruttiger, Susumu Itoh, Fumiko Itoh.

  Transforming growth factor β (TGF-β) is abundantly present in the tumor microenvironment, contributing to cancer progression. However, the regulatory mechanism by which TGF-β affects vascular endothelial cells (ECs) in the tumor microenvironment is not well understood. Herein, we generated tamoxifen-inducible TGF-β type II receptor (TβRII) knockout mice, specifically targeting ECs (TβRIIiΔEC), by crossbreeding TβRII-floxed mice with Pdgfb-icreER mice. We established tumor-bearing mice by transplanting Lewis lung carcinoma (LLC) cells. TβRIIiΔEC mice exhibited increased tumor angiogenesis with fragile new blood vessels, increased bleeding, and hypoxia compared to control mice. Consequently, the compromised tumor microenvironment precipitated a notable surge in circulating tumor cells. Paradoxically, lung metastasis showed a significant decline. This intriguing discrepancy was explained by a reduction in the engraftment between cancer cells and ECs. Disruption of TGF-β signaling downregulated CD44 on ECs, hindering cancer cell adhesion. These findings highlight TGF-β's role in promoting metastasis by modulating EC function.

Keywords:  Biological sciences; Cancer; Cancer systems biology; Natural sciences; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2024.111502
Growth Factors. 2025 Jan 07. 1-11

GDF15 promotes corneal neovascularization and RB cell progression via AKT/ERK signal pathway.

Haijian Zheng, Wen Zheng, Shiliang Cheng, Chunguang Li, Guanglan Liu, Miao Yu, Meng Li, Xinfeng Liu, Fangfang Li, Yanluan Wan, Ling Wang.

  In this study, we aim to explore the involvement of growth differentiation factor 15 (GDF15) in both corneal neovascularization (CNV) and retinoblastoma (RB) progression. Cell migration and proliferation were assessed through Scratch assays and CCK-8 assays. Apoptosis was quantified using flow cytometry. In vitro angiogenesis was evaluated through a tube formation assay. RT-PCR and western blot analyses were employed to assess the angiogenesis-related factors. Results demonstrated that RhGDF15 has a promotional effect on the migration of RB cells. Conversely, si-GDF15 demonstrated an opposite effect. RhGDF15 exhibited an enhancement the tube formation, the levels of HIF-1α and SDF, as well as cell migration. Conversely, si-GDF15 demonstrated an opposite effect. The levels of factors were elevated by rhGDF15 in both HREC and RB cell lines. In conclusion, the downregulation of GDF15 has the potential to inhibit corneal angiogenesis and impede the migration of RB cells. These effects may be dependent on the AKT/ERK pathway.

Keywords:  AKT/ERK; Growth differentiation factor 15; corneal neovascularization; retinoblastoma

DOI:  https://doi.org/10.1080/08977194.2024.2432948
Cells. 2024 Dec 20. pii: 2114. [Epub ahead of print]13(24):

The Tumor Metabolite 5'-Deoxy-5'Methylthioadenosine (MTA) Inhibits Maturation and T Cell-Stimulating Capacity of Dendritic Cells.

Christina Brummer, Katrin Singer, Frederik Henrich, Katrin Peter, Carolin Strobl, Bernadette Neueder, Christina Bruss, Kathrin Renner, Tobias Pukrop, Wolfgang Herr, Michael Aigner, Marina Kreutz.

  Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5'-deoxy-5'methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it is known to inhibit tumor-infiltrating T cells and NK cells. However, the impact of MTA on other intra-tumoral immune cells has not yet been fully elucidated. To study the effects of MTA on dendritic cells (DCs), human monocytes were maturated into DCs with (MTA-DC) or without MTA (co-DC) and analyzed for activation, differentiation, and T cell-stimulating capacity. MTA altered the cytokine secretion profile of monocytes and impaired their maturation into dendritic cells. MTA-DCs produced less IL-12 and showed a more immature-like phenotype characterized by decreased expression of the co-stimulatory molecules CD80, CD83, and CD86 and increased expression of the monocyte markers CD14 and CD16. Consequently, MTA reduced the capability of DCs to stimulate T cells. Mechanistically, the MTA-induced effects on monocytes and DCs were mediated by a mechanism beyond adenosine receptor signaling. These results provide new insights into how altered polyamine metabolism impairs the maturation of monocyte-derived DCs and impacts the crosstalk between T and dendritic cells.

Keywords:  MTA; T cell; adenosine; cancer immunosurveillance; dendritic cells; polyamine; tumor metabolism

DOI:  https://doi.org/10.3390/cells13242114
Sci Rep. 2025 Jan 09. 15(1): 1487

Exercise promotes peripheral glycolysis in skeletal muscle through miR-204 induction via the HIF-1α pathway.

Sang R Lee, Kang Joo Jeong, Moeka Mukae, Jinhee Lee, Eui-Ju Hong.

  The mechanisms underlying exercise-induced insulin sensitization are of great interest, as exercise is a clinically critical intervention for diabetic patients. Some microRNAs (miRs) are secreted from skeletal muscle after exercise where they regulate insulin sensitivity, and have potential as diagnostic markers in diabetic patients. miR-204 is well-known for its involvement in development, cancer, and metabolism; however, its role in exercise-induced glycemic control remains unclear. In the present study, endurance exercise in mice increased miR-204 expression levels in skeletal muscle. In a chronic exercise model, miR-204 expression levels were elevated along with glycolytic enzymes in skeletal muscle. When muscular hypoxia was induced after exercise, miR-204 expression also increased with the upregulation of hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, HIF-1α overexpression led to increased miR-204 expression. Treatment with a miR-204 mimic in C2C12 cells significantly enhanced the glycolysis rate and the mRNA expression of glycolytic enzymes. Notably, intravenous administration of miR-204 in mice increased the glucose clearance rate following refeeding. miR-204 initially elevated blood glucose levels at an early stage of refeeding but later promoted blood glucose reduction as refeeding continued. Additionally, glycolytic enzymes were upregulated in the skeletal muscles of miR-204-injected mice. These findings suggest a novel physiological role for miR-204 in promoting skeletal muscle glycolysis, particularly in situations where insulin action is limited.

Keywords:  Diabetes; Exercise; Glycolysis; miR-204; miRNA

DOI:  https://doi.org/10.1038/s41598-025-85174-0
J Cancer. 2025 ;16(3): 802-811

Elevated Serum IL-6 as a Negative Prognostic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Validation.

Sup Kim, Kyung Hwan Kim, Hee-Won Jung, Eun-Oh Jeong, Han-Joo Lee, Jeanny Kwon, Hyon-Jo Kwon, Seung-Won Choi, Hyeon-Song Koh, Seon-Hwan Kim.

  Background: Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, necessitating the discovery of reliable serum prognostic biomarkers. This study aimed to investigate the prognostic value of serum Interleukin-6 (IL-6) in GBM patients. Methods: Bioinformatics analysis via gene set enrichment analysis was conducted on The Cancer Genome Atlas RNA-seq data to explore the pathways enriched in samples with high IL-6 expression. The Tumor IMmune Estimation Resource database was used to analyze the association between IL-6 expression and immune cell infiltration. To validate the role of IL-6 in a clinical setting, a retrospective cohort study was conducted on newly diagnosed GBM patients. Serum IL-6 levels were repeatedly measured at key milestone time points, and their correlation with survival data was analyzed. Results: Bioinformatics analysis revealed that high IL-6 expression is associated with the activation of procancer pathways, that there is a positive correlation between IL-6 expression and immune cell infiltration in GBM. Between March 2021 and September 2023, 36 GBM patients and their serum IL-6 measurements at various time points were included in the clinical data analyses. Elevated serum IL-6 levels at baseline, with a cutoff of 7pg/mL, were identified in 11 patients (30.6%). In the multivariate analyses for overall survival (OS), elevated IL-6 was a significant risk factor (p = 0.048), along with unfavorable surgical resection (p = 0.039) and O6-methylguanine-DNA methyltransferase promotor unmethylation (p = 0.027). The median actuarial OS of the high initial IL-6 group was significantly shorter than that of the low initial IL-6 group (6.4 vs. 19.7 months, p < 0.001). However, IL-6 levels at other time points were not related to patient prognosis. Conclusion: Elevated IL-6 mRNA expression is correlated with the activation of procancer pathways, increased immune cell infiltration, and poor prognosis in GBM patients. In addition, elevated serum IL-6 at baseline is a negative prognostic factor confirmed in a clinical study. Serum IL-6 may be a potential prognostic biomarker enhancing the management of GBM.

Keywords:  Bioinformatics; Glioblastoma; Interleukin-6

DOI:  https://doi.org/10.7150/jca.104759