bims-stacyt 2025-11-02 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–11–02
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Cancer Manipulates Adjacent Adipose Tissue to Exploit Fatty Acids via HIF-1α/CCL2/PPARα Axis: A Metabolic Circuit to Support Tumor Progression.
Hypoxia-driven metastatic progression in synovial sarcoma: insights from SYO-1 and SW982 models.
Endoplasmic Reticulum Stress Drives VEGF Gene Expression in Monocytic Cells.
Lactate-binding protein DNMT3A in HRMECs promotes angiogenesis by upregulating VEGFA through HIF-1α lactylation.
Metabolic adaptation of glucose-deprived macrophages involves partial gluconeogenesis.
Pre-established ATF4 occupancy and chromatin organization instruct selective transcription activation during integrated stress response.
Dual-Input Regulation of β-Cell Proliferation by ATF6α and Glucose via E2F1.
RIPK3 Protects Against Endothelial Activation and Vascular Permeability in a Mouse Model of Ischemia-Reperfusion Injury.
Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.
MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.

Adv Sci (Weinh). 2025 Oct 29. e15186

Cancer Manipulates Adjacent Adipose Tissue to Exploit Fatty Acids via HIF-1α/CCL2/PPARα Axis: A Metabolic Circuit to Support Tumor Progression.

Jeong-Eun Yun, Jieun Seo, Jiwon Koh, Seock-Ah Im, Ki Yong Hong, Yeseon Son, Do-Won Jeong, Junji Fukuda, Jong-Wan Park, Yang-Sook Chun.

  Rising obesity rates are closely linked to higher risk of cancer, yet the underlying mechanisms are not fully understood. It is previously reported that fatty acids (FAs) released from cancer-associated adipose tissue enhance hypoxia-inducible factor-1α (HIF-1α) expression in cancer cells, promoting tumor progression. Here, it is elucidated that cancer cells manipulate adjacent adipose tissue by secreting C-C chemokine ligand2 (CCL2) to exploit FAs. Activation of HIF-1α induced by FA influx increases CCL2 expression in cancer cells, which subsequently leads to lipolysis in nearby adipose tissue by activating peroxisome proliferator-activated receptor alpha (PPARα) signaling. This activation in adipose tissue results in the release of FAs into the tumor microenvironment. The increased lipid supply to tumor reactivates the FA/HIF-1α/CCL2 axis in cancer cells, further accelerating tumor growth and CCL2 secretion. This establishes a positive feedback loop between tumor and adjacent adipose tissue, which enhances cancer progression. This crosstalk is validated by using a polydimethylsiloxane-based 3D coculture system and in vivo models. In obese mice, this reciprocal signaling accelerated tumor progression, whereas intra-tumoral injection of CCL2-neutralizing antibody significantly suppressed it. These findings reveal a metabolic circuit for tumor survival and disrupting this interaction may provide promising therapeutic targets, particularly for obese cancer patients.

Keywords:  CCL2; HIF‐1α; PPARα; cancer; obesity

DOI:  https://doi.org/10.1002/advs.202515186
BMC Cancer. 2025 Oct 31. 25(1): 1680

Hypoxia-driven metastatic progression in synovial sarcoma: insights from SYO-1 and SW982 models.

Maria Fueth, Jannis Christoffel, Kamran Harati, Felix Reinkemeier, Sonja Verena Schmidt, Marius Drysch, Flemming Puscz, Jannik Hinzmann, Tom Alexander Huyghebaert, Alexander Fiedler, Marcus Lehnhardt, Christoph Wallner, Yonca Steubing.

   BACKGROUND: Synovial sarcoma (SS) is a rare but aggressive soft tissue malignancy characterized by a high rate of pulmonary metastasis and limited response to conventional therapies. Hypoxia, a common feature of tumor microenvironment, has been implicated in cancer progression, yet its specific contribution to metastatic dissemination in SS remains insufficiently characterized.
METHODS: We investigated the effects of hypoxia on metastatic behavior in two SS cell lines: SYO-1 (SS18-SSX2 fusion-positive) and SW982 (fusion-negative). Cells were cultured under hypoxic (O₂ < 1%) and normoxic (21% O₂) conditions, followed by reoxygenation. Expression of hypoxia-responsive and metastasis-related genes (e.g., HIF-1α, CA9, VEGF, IGF2, ADM, YB-1, TGF-β1) was assessed via qRT-PCR. To evaluate in vivo metastatic potential, a lung colonization model was established by injecting pretreated cells into the tail veins of immunodeficient (NMRI nu/nu) mice.
RESULTS: Hypoxia significantly upregulated canonical HIF-1α targets in both cell lines, with SYO-1 showing stronger and more sustained induction, particularly of CA9 and VEGF. In vivo, SYO-1 cells formed significantly more micrometastatic lung lesions compared to SW982, with distinct perivascular clustering and signs of early intravasation. SW982 cells exhibited limited, diffuse infiltration and lower hypoxia-induced gene activation. These differences suggest that the SS18-SSX fusion may synergize with hypoxia signaling to enhance metastatic potential. Notably, HIF-1α, CA9, and IGF2 expression correlated with metastatic capacity, while TGF-β1 expression declined under hypoxia, indicating a dynamic regulation of prometastatic pathways.
CONCLUSION: Our findings demonstrate that hypoxia promotes SS metastasis through activation of HIF-1α and related pathways. Fusion-positive SS cells appear particularly responsive to hypoxic cues, suggesting that targeting hypoxia-induced signaling could be a promising strategy to inhibit metastasis in SS. These results provide mechanistic insight into SS progression and support the integration of hypoxia-targeted therapies into future treatment strategies.

Keywords:  Hypoxia; Hypoxia-induced tumor progression; Metastasis; SS18-SSX fusion; Synovial sarcoma; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12885-025-15125-5
Curr Issues Mol Biol. 2025 Oct 13. pii: 839. [Epub ahead of print]47(10):

Endoplasmic Reticulum Stress Drives VEGF Gene Expression in Monocytic Cells.

Fatemah Bahman, Taha Nadeem, Abdulrahman Alayyaf, Ashraf Al Madhoun, Fahd Al-Mulla, Sardar Sindhu, Rasheed Ahmad.

  Obesity is characterized by chronic low-grade inflammation and oxidative stress, conditions that disrupt metabolic homeostasis and promote vascular endothelial growth factor (VEGF) expression. While hypoxia and fatty acid-induced oxidative stress are known regulators of VEGF, the contribution of endoplasmic reticulum (ER) stress in monocytic cells remains unclear. In this study, we investigated the interplay between ER stress and metabolic stress in regulating VEGF expression using THP-1 monocytic cells. Metabolic stress was induced by palmitic acid (PA) and ER stress by thapsigargin (TG). Co-treatment with PA and TG significantly increased VEGF mRNA and protein levels compared to PA alone. This effect was accompanied by enhanced reactive oxygen species (ROS) production and upregulation of ER stress markers, including CHOP, ATF6, and IRE1. Pretreatment with the antioxidant curcumin markedly reduced VEGF expression and ROS levels, indicating a ROS-dependent mechanism. Additionally, PA+TG co-treatment elevated transcripts of antioxidant defense genes such as SOD2 and NRF2, suggesting a compensatory cellular response to oxidative stress. These findings demonstrate that ER stress amplifies VEGF induction in monocytic cells under lipotoxic conditions through ROS-mediated pathways, highlighting a potential mechanism linking metabolic stress, inflammation, and angiogenesis in obesity-related disorders.

Keywords:  ROS; VEGF; inflammation; metabolic stress; obesity

DOI:  https://doi.org/10.3390/cimb47100839
Genome Biol. 2025 Oct 30. 26(1): 377

Lactate-binding protein DNMT3A in HRMECs promotes angiogenesis by upregulating VEGFA through HIF-1α lactylation.

Xiaotang Wang, Jiaxing Huang, Wei Fan, Na Li, Hui Yang, Wenxian Yang, Wanqian Li, Ruonan Li, Jiangyi Liu, Xingran Li, Qian Zhou, Shengping Hou.

BACKGROUND: Ocular neovascularization is a leading cause of blindness. Hypoxia is associated with retinal angiogenesis. Hypoxia results in lactate accumulation, which typically precedes protein lactylation, and this plays a crucial role in ocular neovascularization. However, the underlying mechanism remains unclear. Here, we investigate the role of the DNA methyltransferase, DNMT3A, in regulating lactylation following hypoxia in ocular neovascularization.
RESULTS: DNMT3A controls endothelial cell angiogenesis via regulating lactate-derived HIF-1α lactylation. During oxygen-induced retinopathy progression, we detected increased levels of DNMT3A, HIF-1α lactylation, and vascular endothelial growth factor (VEGF) in endothelial cells. Exogenous lactate administration significantly enhances vascularization, while inhibiting lactate uptake in the presence or absence of DNMT3A prevents endothelial cell angiogenesis and attenuates HIF-1α lactylation. We demonstrate that modulating DNMT3A expression alters HIF-1α lactylation levels, influencing angiogenesis in vitro and in vivo.
CONCLUSIONS: DNMT3A facilitates lactate transport into the nucleus, where it promotes VEGFA upregulation through HIF-1α lactylation, thereby stimulating endothelial cell angiogenesis. Targeting the lactate-DNMT3A/HIF-1α lactylation/VEGFA pathway could provide new therapeutic strategies for treating ocular neovascularization disorders.

DOI: https://doi.org/10.1186/s13059-025-03845-7
Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2419568122

Metabolic adaptation of glucose-deprived macrophages involves partial gluconeogenesis.

Katharina Schindlmaier, Theresa Haitzmann, Visnja Bubalo, Barbara Konrad, Joseph Jelwan, Gabriele Bluemel, Sonja Rittchen, Vanessa Jäger, Michael A Dengler, Luka Brcic, Jörg Lindenmann, Leigh M Marsh, Thomas O Eichmann, Alexander Kirchmair, Zlatko Trajanoski, Julia Kargl, Cristina Muñoz-Pinedo, Katharina Leithner.

  Macrophages are recruited to sites of infection contributing to the killing of bacteria, but also to malignant tumors, where they promote angiogenesis and suppress antitumor immune responses. The metabolic microenvironment in tumors is frequently depleted of important nutrients such as glucose. Here, we investigated metabolic adaptation strategies of macrophages to glucose deprivation using stable isotopic tracing. Lactate production was decreased, potentially indicating a reduction of glycolysis. In contrast, the contribution of glutamine to the tricarboxylic acid cycle via α-ketoglutarate and reductive carboxylation were increased. Moreover, gluconeogenesis, the reverse pathway of glycolysis, was activated in glucose-deprived macrophages, proceeding partially to the generation of glycolytic intermediates and glycerol-3-phosphate. The partial gluconeogenesis pathway was abrogated in human and murine macrophages lacking the initial gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK2, mitochondrial isoform). Partial gluconeogenesis was higher in anti-inflammatory, interleukin-4-stimulated compared to proinflammatory, interferon-γ/lipopolysaccharide-stimulated macrophages. Single-cell analysis and immunostaining revealed expression of PCK2 in macrophages from both lung cancer and normal lung. Low glucose conditions only partially modulated macrophage phenotypes, leading to reduced CD80 surface marker levels in proinflammatory, and enhanced vascular endothelial growth factor expression in anti-inflammatory macrophages. Our study reveals partial gluconeogenesis in glucose-deprived macrophages and shows that this versatile type of immune cells exhibits remarkable metabolic flexibility.

Keywords:  glucose deprivation; glycolysis; macrophages; metabolism; partial gluconeogenesis

DOI:  https://doi.org/10.1073/pnas.2419568122
Nat Commun. 2025 Oct 28. 16(1): 9502

Pre-established ATF4 occupancy and chromatin organization instruct selective transcription activation during integrated stress response.

Peipei Jiang, Qian Bian.

Cells rapidly and extensively remodel their transcriptome in response to stress to restore homeostasis, but the underlying mechanisms are not fully understood. Here, we characterize the dynamic changes in transcriptome, epigenetics, and 3D genome organization during the integrated stress response (ISR). ISR induction triggers widespread transcriptional changes within 6 h, coinciding with increased binding of ATF4, a key transcriptional effector. Notably, ATF4 binds to hundreds of genes even under non-stress conditions, priming them for stronger activation upon stress. The transcriptional changes at ATF4-bound sites during ISR do not rely on increased H3K27 acetylation, chromatin accessibility, or rewired enhancer-promoter looping. Instead, ATF4-mediated gene activation is linked to the redistribution of CEBPγ from non-ATF4 sites to a subset of ATF4-bound regions, likely by forming an ATF4/CEBPγ heterodimer. CEBPγ preferentially targets the sites pre-occupied by ATF4, as well as genomic regions exhibiting a unique higher-order chromatin structure signature. Thus, the transcriptional responses during ISR are largely pre-wired by intrinsic chromatin properties. These findings provide critical insights into transcriptional remodeling during ISR with broader implications for other stress responses.

DOI: https://doi.org/10.1038/s41467-025-64577-7
Diabetes. 2025 Oct 31. pii: db250279. [Epub ahead of print]

Dual-Input Regulation of β-Cell Proliferation by ATF6α and Glucose via E2F1.

Huguet V Landa-Galvan, Thalia A Castro, Jahi J Noel, Gabriel Avila Llamas, Rohit B Sharma, Laura C Alonso.

ARTICLE HIGHLIGHTS: Endoplasmic reticulum stress response mediator activating transcription factor 6 (ATF6α) increases pancreatic β-cell proliferation in a glucose-dependent manner, but the mechanism remains unknown. ATF6α activation upregulated mRNA and protein expression of E2F1, a key G1/S phase transition regulator; however, E2F1 activity only increased in high glucose. Glucose dependence of E2F1 activity was mediated by cyclin-dependent kinase 4/6 phosphorylation of retinoblastoma (Rb) protein, derepressing E2F1 in high glucose. Generalized endoplasmic reticulum stressor thapsigargin increased E2F1 abundance in an ATF6-dependent manner. ATF6α increased E2F1 expression in human β-cells and increased human β-cell proliferation when cyclin-dependent kinase 6 (CDK6) was coexpressed.

DOI: https://doi.org/10.2337/db25-0279
Arterioscler Thromb Vasc Biol. 2025 Oct 30.

RIPK3 Protects Against Endothelial Activation and Vascular Permeability in a Mouse Model of Ischemia-Reperfusion Injury.

Charmain F Johnson, Christopher M Schafer, Kathryn Y Burge, Brian G Coon, Hala Chaaban, Courtney T Griffin.

   BACKGROUND: RIPK3 (receptor-interacting protein kinase 3) has context-specific roles that are frequently associated with cellular damage and death. We previously found that hypoxia can trigger elevated levels of RIPK3 in endothelial cells (ECs), which contributes to lethal vascular rupture during mouse embryonic development. However, it is unknown whether elevated RIPK3 likewise compromises endothelial barrier function in adult vasculature under hypoxic conditions such as ischemia-reperfusion (I/R) injury.
METHODS: Twelve-week-old male and female littermate control or inducible EC-specific Ripk3 knockout (Ripk3iECKO) mice were exposed to surgical intestinal I/R injury. Clodronate liposomes were used to reduce circulating monocytes in vivo. Immortalized murine EC (MS1) and murine macrophage lines (BMA3.1A7) were used for in vitro experiments.
RESULTS: Ripk3iECKO mice displayed an unexpected increase in small intestinal vascular permeability after I/R injury, rather than the decrease we predicted. Subsequent analyses using multiplex cytokine assays revealed significantly elevated levels of IL-6 (interleukin-6) in the serum and small intestinal tissue of I/R-injured Ripk3iECKO mice. Upon TNFα (tumor necrosis factor-alpha) stimulation of immortalized murine Ripk3 knockout ECs grown in vitro, we found increased transcription and secretion of IL-6. These cells also expressed elevated levels of VCAM-1 (vascular cell adhesion molecule-1), which was likewise upregulated in the small intestines of Ripk3iECKO mice. Using an IL-6 neutralizing antibody, we found that IL-6 triggered VCAM-1 elevation in Ripk3 knockout cells. This VCAM-1 expression correlated with enhanced macrophage binding to Ripk3 knockout cells and increased accumulation of leukocytes in Ripk3iECKO small intestines following I/R injury. Importantly, reduction of circulating monocytes with clodronate liposomes led to rescue of IR injury-induced vascular permeability in Ripk3iECKO mice.
CONCLUSIONS: Endothelial RIPK3 suppresses EC activation and inflammation associated with IL-6 and VCAM-1 elevation to protect the vascular barrier in the context of intestinal I/R injury. Thus, endothelial RIPK3 plays surprisingly beneficial roles that reduce I/R injury-induced vascular dysfunction.

Keywords:  cytokines; inflammation; interleukin-6; mice; monocytes

DOI:  https://doi.org/10.1161/ATVBAHA.125.322977
Mol Biomed. 2025 Oct 27. 6(1): 87

Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.

Yongrui Hai, Ruizhuo Lin, Weike Liao, Shuo Fu, Renming Fan, Guiquan Ding, Junyan Zhuang, Bingjie Zhang, Yi Liu, Junke Song, Gaofei Wei.

  Cancer cells rely heavily on de novo pyrimidine synthesis. Inhibiting pyrimidine metabolism directly suppresses tumor growth and fosters immune activation within the tumor microenvironment. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine synthesis pathway. Inhibiting DHODH can reverse immune suppression and trigger a mild innate immune response. However, the impact of DHODH inhibition on natural killer (NK) cells remains to be explored. In this study, we found that DHODH inhibition promoted NK cell infiltration into tumors efficiently. Mechanistically, DHODH suppression induced mitochondrial oxidative stress, leading to mitochondrial DNA (mtDNA) release into the cytoplasm through voltage-dependent anion channel (VDAC) oligomerization and caspase-3 activation. This subsequently activated the stimulator of interferon gene (STING) pathway, triggered ferroptosis, and induced gasdermin E (GSDME) mediated pyroptosis in cancer cells. These changes collectively facilitated NK cell recruitment. Furthermore, infiltrated NK cells enhanced GSDME-dependent pyroptosis in tumor cells through granzyme release, establishing a positive feedback loop that amplified anti-tumor immunity. Additionally, we developed EA6, a novel DHODH inhibitor that is more effective at promoting NK cell infiltration. In summary, this study reveals that targeting pyrimidine metabolism activates a novel mechanism involving pyroptosis-ferroptosis crosstalk and STING pathway activation to enhance NK cell-mediated immunity. These finding opens new avenues for enhancing the efficacy of targeted nucleotide metabolism in cancer therapy.

Keywords:  CGAS-STING pathway; DHODH; NK cells; Pyrimidine metabolism; Pyroptosis

DOI:  https://doi.org/10.1186/s43556-025-00339-7
Cell Mol Life Sci. 2025 Oct 28. 82(1): 371

MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.

Bin Zhang, Anran Xu, Haowei Wang, Wei Yan, Qing Zhang, Shuang Wang.

  Lactate is an abundant oncometabolite in the tumor microenvironment (TME). Lactate driven by metabolic reprogramming leads to acidic microenvironment formation to promote the immune evasion of tumor cells and reduce the effectiveness of immunotherapy for patients with tumors. The expression of mitochondrial pyruvate carrier (MPC) is crucial for pyruvate metabolism, and its dysregulation can lead to the formation of an acidic microenvironment caused by excessive lactic acid. However, the impact of MPC on tumor metabolic processes and biological behavior, as well as how lactate impacts immunosuppression, remains unclear. Here, we found that MPC1 and MPC2, two subunits of MPC, were downregulated in patients with colorectal cancer (CRC). Co-overexpression of MPC1 and MPC2 decreased lactate levels and inhibited cell proliferation, migration and invasion in vitro and tumor growth in vivo in the setting of CRC. Knockdown of MPC1 or MPC2 increased lactate levels and promoted the proliferation, migration and invasion of CRC cells. Mechanistically, the accumulation of lactate promotes the elevation of histone lactylation levels, and MPC regulates the expression of CD33, a marker of dendritic cell (DC) maturation, via histone lactylation, decreasing CD8+ T cell functions. In addition, the overexpression of MPC increased the therapeutic effect of the anti-PD-1 antibody. Our findings reveal that MPC downregulation-mediated lactate production impacts DC maturation via histone lactylation-dependent transcriptional regulation to impair CD8+ T cell responses, suggesting that targeting MPC could enhance immunotherapy efficacy by modulating the TME.

Keywords:  CD33; Colorectal cancer; Dendritic cell; Histone lactylation; Mitochondrial pyruvate transporter carrier

DOI:  https://doi.org/10.1007/s00018-025-05881-9