bims-stacyt 2025-07-06 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–07–06
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Machine learning-guided single-cell multiomics uncovers GDF15-driven immunosuppressive niches in NSCLC: A translational framework for overcoming anti-PD-1 resistance.
Mutant p53 exploits enhancers to elevate immunosuppressive chemokine expression and impair immune checkpoint inhibitors in pancreatic cancer.
PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.
Adipocytes-induced ANGPTL4/KLF4 axis drives glycolysis and metastasis in triple-negative breast cancer.
Hypoxia preconditioned plasma increases the expression of growth factors to accelerate diabetic wound healing by promoting angiogenesis.
Astrocytic Glucose Sensing Drives Synaptic Depression under Metabolic Stress.
The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.
Inhibition of the Na+-glucose transporter SGLT2 reduces glucose uptake and IFNγ release from activated human CD4+ T cells.
Triglycerides are an important fuel reserve for synapse function in the brain.

Transl Oncol. 2025 Jun 28. pii: S1936-5233(25)00190-1. [Epub ahead of print]59 102459

Machine learning-guided single-cell multiomics uncovers GDF15-driven immunosuppressive niches in NSCLC: A translational framework for overcoming anti-PD-1 resistance.

Xianfei Zhang, Zhengxin Yin, Xueyu Chen, Nengchong Zhang, Shengjia Yu, Congcong Zhu, Lianggang Zhu, Liulan Shao, Bin Li, Runsen Jin, Hecheng Li.

  Immune checkpoint blockade (ICB) has transformed non-small cell lung cancer (NSCLC) treatment, but durable clinical responses remain limited, underscoring the need for robust predictive biomarkers. We integrated multiomics profiling with machine learning to systematically identify determinants of ICB efficacy. Comparative evaluation of 22 survival algorithms across four NSCLC cohorts (n=156) led to the development of an Accelerated Oblique Random Survival Forest model, which outperformed conventional Cox regression and deep learning methods in predictive accuracy (training C-index=0.864; test C-index=0.748). Single-cell RNA sequencing of an immunotherapy-treated cohort revealed that high-risk tumors harbor malignant epithelial subclusters expressing growth differentiation factor 15 (GDF15), a transforming growth factor-β superfamily member implicated in immune evasion. Single-cell non-negative matrix factorization identified GDF15 as a network hub regulating proliferative dominance. External validation using melanoma cohorts (GSE91061) confirmed the pan-cancer predictive relevance of GDF15 and its associated tumor cluster. Functional studies utilizing GDF15-knockdown Lewis lung carcinoma cells showed no significant effect on intrinsic tumor proliferation or growth under immune stress (both p>0.05). GDF15 deletion significantly potentiated PD-1 inhibitor efficacy in vivo, reducing tumor mass by 94.41±6.53 % (SH1) and 94.54±5.21 % (SH2) compared with 3.39±54.90 % in empty vector controls (p<0.01 for all comparisons). CD8+ T cell infiltration was also substantially enhanced (81.62±4.79 % [SH1] and 123.50±10.02 % [SH2] vs. 29.63±22.17 % [EV], p<0.05). These findings implicate GDF15 as a regulator of the immunosuppressive tumor microenvironment. Our findings position GDF15 as a first-in-class biomarker for predicting ICB resistance; they establish a translational framework that bridges computational prediction with single-cell mechanistic insights to inform NSCLC immunotherapy.

Keywords:  Growth differentiation factor 15; Immunotherapy; Lung cancer; Programmed cell death protein 1

DOI:  https://doi.org/10.1016/j.tranon.2025.102459
Immunity. 2025 Jun 25. pii: S1074-7613(25)00274-2. [Epub ahead of print]

Mutant p53 exploits enhancers to elevate immunosuppressive chemokine expression and impair immune checkpoint inhibitors in pancreatic cancer.

Dig B Mahat, Heena Kumra, Sarah A Castro, Emily Metcalf, Kim Nguyen, Ryo Morisue, William W Ho, Ivy Chen, Brandon Sullivan, Leon H Yim, Arundeep Singh, Jiayu Fu, Sean K Waterton, Yu-Chi Cheng, Enrico Moiso, Vikash P Chauhan, Hernandez Moura Silva, Stefani Spranger, Rakesh K Jain, Phillip A Sharp.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by activating KRAS mutations and TP53 alterations. TP53 missense mutations lose their wild-type tumor-suppressor function. Here, we studied whether p53 missense mutations have potential gain-of-function oncogenic roles and their impact on cancer-cell-intrinsic gene expression and the tumor immune microenvironment (TME) in PDAC. p53R172H established an immunosuppressive TME and impaired the efficacy of immune checkpoint inhibitors (ICIs) by regulating a distinct set of chemokines. Among these, tumor-specific reduction of Cxcl1, which encodes a chemoattractant for neutrophils, promoted T cell infiltration and decreased tumor growth. Mechanistically, p53R172H occupied the distal enhancers of Cxcl1 and amplified its expression. These enhancers were responsible for Cxcl1 expression and were essential for its immunosuppressive function. Nuclear factor κB (NF-κB) was a critical cofactor required for p53R172H occupancy at these enhancers. Thus, a common mutation in a tumor-suppressor transcription factor appropriates enhancers, thereby stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC.

Keywords:  Cxcl1; PDAC; PRO-seq; chemokine; enhancer; immune checkpoint inhibitors; mutant p53; myeloid-derived suppressor cells; nascent RNA sequencing; neutrophils

DOI:  https://doi.org/10.1016/j.immuni.2025.06.005
Cancer Res. 2025 Jul 03.

PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.

Beatriz Parejo-Alonso, David Barneda, Sara Maria David Trabulo, Sarah Courtois, Sara Compte-Sancerni, Jelena Zurkovic, Laura Ruiz-Cañas, Quan Zheng, Jiajia Tang, Matthias M Gaida, Ulf Schmitz, Pilar Irun, Laure Penin-Peyta, Shanthini Mary Crusz, Petra Jagušt, Pilar Espiau-Romera, Alba Royo-García, Andrés Gordo-Ortiz, Mariia Yuneva, Meng-Lay Lin, Shenghui Huang, Ming-Hsin Yang, Angel Lanas, Bruno Sainz, Christoph Thiele, Christopher Heeschen, Patricia Sancho.

The pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells employ various adaptive mechanisms that may represent therapeutic targets. Here, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPAR-δ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPAR-δ. Specifically, PPAR-δ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacological inhibition of PPAR-δ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPAR-δ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a pro-metastatic phenotype in PDAC, suggesting that PPAR-δ inhibition could serve as a therapeutic strategy to combat PDAC progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3475
J Exp Clin Cancer Res. 2025 Jul 04. 44(1): 192

Adipocytes-induced ANGPTL4/KLF4 axis drives glycolysis and metastasis in triple-negative breast cancer.

Dou Yin, Nana Fang, Yaling Zhu, Xiaoqing Bao, Juan Yang, Qingyu Zhang, Ruimeng Wang, Jiahui Huang, Qibing Wu, Fang Ma, Xiaohui Wei.

   BACKGROUND: The adipocyte-rich tumor microenvironment (TME) is recognized as a key factor in promoting cancer progression. A distinct characteristic of peritumoral adipocytes is their reduced lipid content and the acquisition of a proinflammatory phenotype. However, the underlying mechanisms by which adipocytes rewire metabolism and boost tumor progression in triple-negative breast cancer (TNBC) remain poorly understood.
METHODS: We utilized transcriptomic analysis, bioinformatic analysis, metabolic flux analysis, protein-protein docking, gene and protein expression profiling, in vivo metastasis analysis and breast cancer specimens to explore how adipocytes reprogram tumor metabolism and progression in TNBC.
RESULTS: Our findings reveal that Angiopoietin-like 4 (ANGPTL4) exhibits significantly higher expression levels in adipocyte-rich tumor circumstance compared to the symbiotic environment lacking of adipocyte. Furthermore, ANGPTL4 expression in tumor cells is essential for adipocyte-driven glycolysis and metastasis. Interleukin 6 (IL-6), enriched in cancer-associated adipocytes, and lipolysis-derived free fatty acids (FFAs) released from adipocytes, amplify ANGPTL4-mediated glycolysis and metastasis through activation of STAT3 and PPARα pathways in TNBC cells. Additionally, ANGPTL4 interacts with transcription factor KLF4 and enhances KLF4 activity, which further drives glycolysis and metastasis, whereas KLF4 knockdown attenuates migration and glycolysis in TNBC cells. Importantly, Elevated ANGPTL4 and KLF4 expression was observed in metastatic breast cancer specimens compared to non-metastatic cases and was positively correlated with poor prognosis.
CONCLUSION: Collectively, our results uncover a complex metabolic interaction between adipocytes and TNBC cells that promotes tumor aggressiveness. ANGPTL4 emerges as a key mediator in this process, making it a promising therapeutic target to inhibit TNBC progression.

Keywords:  ANGPTL4; Adipocytes; KLF4; Lipolysis; Triple-Negative Breast Cancer

DOI:  https://doi.org/10.1186/s13046-025-03458-9
Sci Rep. 2025 Jul 02. 15(1): 23154

Hypoxia preconditioned plasma increases the expression of growth factors to accelerate diabetic wound healing by promoting angiogenesis.

Guanghong Zhou, Min Tao, Jie Zhu, Shengbing Li, Lili Zhang.

  Hypoxia preconditioned plasma (HPP) is generated by cultivating blood under hypoxic conditions, allowing blood cells to naturally regulate the production of growth factors in response to hypoxia, which seems ideal for diabetic wound treatment. This study aims to verify the efficacy and underlying mechanism of HPP on diabetic wound healing. The concentrations of angiogenesis-related factors (VEGF, PDGF, EGF, IGF, TSP1, PF4) measured by ELISA were significantly increased in HPP. In vitro, HPP promoted the proliferation and migration of HUVECs and HSF, and enhanced the tube formation of HUVECs. In vivo, HPP promotes wound angiogenesis and collagen deposition, significantly accelerating diabetic wound healing (84 ± 10% vs. 65 ± 20%, p < 0.01). Furthermore, western blot and qPCR results showed that both in cells and wounds, the expression of pro-angiogenic factors, as well as p-AKT, was increased in HPP. These findings suggest that HPP benefits diabetic wound healing and may represent a promising therapeutic approach for diabetic wound healing.

Keywords:  AKT signaling pathway; Angiogenesis; Diabetic wound; Growth factor; Hypoxia

DOI:  https://doi.org/10.1038/s41598-025-04665-2
Aging Dis. 2025 Jun 19.

Astrocytic Glucose Sensing Drives Synaptic Depression under Metabolic Stress.

Andrés M Baraibar, Carlos G Ardanaz, Susana Mato, Paulo Kofuji, Alfonso Araque, Maite Solas.

Glucose is the primary energy source for the brain, and its continuous supply is essential for neuronal function. Astrocytes play a pivotal role in brain energy metabolism by mediating glucose uptake, sensing metabolic fluctuations, and modulating synaptic activity. However, astrocyte responses to transient glucose deprivation remain incompletely understood. Here, we demonstrate that astrocytic glucose uptake is crucial for network adaptation to metabolic stress. Using electrophysiology and calcium imaging approaches, we show that glucose deprivation depresses hippocampal synaptic transmission through an astrocyte-dependent mechanism that involves decreased glucose transporter 1 (GLUT1)-facilitated extracellular glucose uptake, intracellular calcium elevations, and ATP/adenosine-mediated signaling, which leads to excitatory neurotransmission depression via A1 receptors. Moreover, astrocyte-specific GLUT1 depletion prevents astrocytic responses to glucose deprivation and precludes the effects of glucose deprivation on synaptic transmission, thereby indicating that GLUT1-dependent glucose uptake is involved in astrocyte-mediated modulation of synaptic function. These findings extend the concept of astrocytic metabolic regulation beyond regions canonically classified as glucose-sensing and establish astrocytes as key integrators of energy availability and synaptic function. Our study provides new insights into the role of astrocytes in brain energy homeostasis and identifies potential therapeutic targets for metabolic disorders affecting the nervous system.

DOI: https://doi.org/10.14336/AD.2025.0507
iScience. 2025 Jul 18. 28(7): 112714

The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.

Meiricris Tomaz da Silva, Anirban Roy, Anh Tuan Vuong, Aniket S Joshi, Cristeena Josphien, Meghana V Trivedi, Sajedah M Hindi, Vihang A Narkar, Ashok Kumar.

  Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting. The TWEAK-Fn14 system regulates muscle mass in diverse conditions. However, its role in the regulation of muscle mass during cancer cachexia remains less understood. Here, we demonstrate that the levels of Fn14 are induced in skeletal muscle of multiple mouse models of cancer cachexia. Muscle-specific deletion of Fn14 reduces myofiber atrophy in mouse models of pancreatic and lung cancer cachexia. Silencing of Fn14 in KPC pancreatic cancer cells prior to their implantation in mice attenuates tumor growth without affecting myofiber size. Muscle-specific deletion of Fn14 reduces the gene expression of various components of the PERK and IRE1α arms of the unfolded protein response during KPC tumor growth. The inhibition of PERK improves protein synthesis and average myotube diameter in TWEAK-treated cultures. Altogether, our study suggests that the inhibition of TWEAK/Fn14 signaling can attenuate tumor growth and muscle wasting during cancer cachexia.

Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112714
Front Immunol. 2025 ;16 1576216

Inhibition of the Na+-glucose transporter SGLT2 reduces glucose uptake and IFNγ release from activated human CD4+ T cells.

Zhe Jin, Hayma Hammoud, Amol K Bhandage, Stasini Koreli, Azazul Islam Chowdhury, Peter Bergsten, Bryndis Birnir.

  Glucose uptake in activated CD4+ T cells is essential for increased metabolic needs, synthesis of biomolecules and proliferation. Although, facilitated glucose transport is the predominant route for glucose entry at the time of activation, here we demonstrate role for the sodium-dependent glucose transporter SGLT2. By 72 h after activation, SGLT2 is expressed and functional in the human CD4+ T cells. SGLT2 inhibitors, phlorizin and empagliflozin decreased glucose uptake into the human CD4+ T cells compared to untreated cells. Phlorizin (25 μmol/L) reduced glycolysis at 5.6 mmol/L glucose and IFNγ levels at both 5.6 mmol/L and 16.7 mmol/L glucose. In contrast, empagliflozin (0.5 μmol/L) only decreased IFNγ levels in 16.7 mmol/L glucose. GABA enhanced phlorizin inhibition at both 5.6 mmol/L and 16.7 mmol/L glucose in the presence of insulin. Insulin strengthens GABAA receptors signaling in CD4+ T cells. The results are consistent with expression of SGLT2 after activation of human CD4+ T cells, that facilitates concentrating glucose uptake into the cells, enabling enhanced release of inflammatory molecules like IFNγ. Importantly, inhibition of SGLT2 decreases IFNγ release.

Keywords:  GLUT1; IFNγ; SGLT2; T cells; empagliflozin; glucose uptake; immunomodulation; phlorizin

DOI:  https://doi.org/10.3389/fimmu.2025.1576216
Nat Metab. 2025 Jul 01.

Triglycerides are an important fuel reserve for synapse function in the brain.

Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.

Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.

DOI: https://doi.org/10.1038/s42255-025-01321-x