bims-stacyt 2025-12-07 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–12–07
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation.
Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle-tumor metabolic competition.
FGF19 in Solid Tumors: Molecular Mechanisms, Metabolic Reprogramming, and Emerging Therapeutic Opportunities.
Asparagine endopeptidase prompts breast cancer-related pericardial calcification by regulating IGF2 and integrin αvβ5.
PRKCSH deficiency promotes an anti-tumor immune microenvironment via UPR activation and M1 macrophage polarization.
Nuclear receptor ERRγ acts as a key transcriptional regulator of hepatic LCN2 expression in CCl4-induced acute liver injury.
The Proinflammatory Secretome of Senescent Cells Can Be Controlled by a HIF2A-Dependent Upregulation and a FURIN-Dependent Cleavage of the ANGPTL4 Secreted Factor.
Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.
KRASG12D/G13D-USP15 axis promotes TGF-β/SMAD signaling and glycolytic flux to accelerate NSCLC pathogenesis.
Spatiotemporal profiling of modification-specific proteome secretion uncovers an itaconation-activated tyrosine kinase.

Nat Aging. 2025 Dec 03.

Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation.

Bingjie Guan, Mantang Zhou, Weixing Dai, Jing Zhang, Bowen Xie, Yushuai Mi, Xin Zhang, Ping Wei, Youdong Liu, Shanbao Li, Haonan Guan, Xiaoming Zhang, Sanjun Cai, Dawei Li, Dongwang Yan, Senlin Zhao.

One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer.

DOI: https://doi.org/10.1038/s43587-025-01023-9
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2508707122

Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle-tumor metabolic competition.

Brooks P Leitner, Andin E Fosam, Won D Lee, Kaylee Zilinger, Susana C B R Nakandakari, Xinyi Zhang, Rafael C Gaspar, Wanling Zhu, Curtis J Perry, Joshua D Rabinowitz, Rachel J Perry.

  Higher exercise capacity and regular exercise training improve cancer prognosis at all stages of disease. However, the metabolic adaptations to aerobic exercise training that mediate tumor-host interactions are poorly understood. Here, we demonstrate that voluntary wheel running slows tumor growth and repartitions glucose uptake and oxidation to skeletal and cardiac muscle and away from breast and melanoma tumors in mice. Further, prehabilitation induces repartitioning of glucose metabolism in obese mice: Uptake and oxidation of glucose are enhanced in skeletal and cardiac muscle, and reduced in tumors. These increases in muscle glucose metabolism and reductions in tumor glucose metabolism, correlated with slower tumor progression. Using [U-13C6] glucose infusion, we show that exercise increases the fractional contribution of glucose to oxidative metabolism in muscle while reducing it in tumors, suggesting that aerobic exercise shifts systemic glucose metabolism away from the tumor microenvironment and toward metabolically active tissues. Transcriptional analysis revealed downregulation of mTOR signaling in tumors from exercised mice. Collectively, our findings suggest that voluntary exercise may suppress tumor progression by enhancing host tissue glucose oxidation and limiting tumor glucose availability, supporting a model in which exercise-induced metabolic competition constrains tumor energetics.

Keywords:  breast cancer; exercise; melanoma; tumor metabolism

DOI:  https://doi.org/10.1073/pnas.2508707122
Theranostics. 2026 ;16(1): 345-397

FGF19 in Solid Tumors: Molecular Mechanisms, Metabolic Reprogramming, and Emerging Therapeutic Opportunities.

Jiayi Xu, Peng Sun, Wenjing Zhu, Xinlin Liu, Leina Ma.

  Fibroblast growth factor 19 (FGF19), the human orthologue of murine FGF15, is an endocrine FGF that signals through the FGFR4-β-Klotho receptor complex to regulate bile acid synthesis, glucose and lipid metabolism, and thermogenesis. Beyond its physiological role in metabolic homeostasis, aberrant expression of FGF19 has been increasingly implicated in the initiation and progression of solid tumors. Mechanistically, FGF19 drives signaling cascades that sustain proliferation, invasion, and metabolic reprogramming, while also promoting epithelial-mesenchymal transition, angiogenesis, and immunosuppression to facilitate metastasis. These pleiotropic activities highlight FGF19 as a compelling therapeutic target, and several FGFR4-directed inhibitors have entered clinical evaluation. However, challenges remain, including on-target toxicities, limited selectivity and adaptive resistance. In this review, discuss the molecular mechanisms by which FGF19 shapes tumor biology, evaluate the current status of therapeutic strategies targeting the FGF19-FGFR4 axis, and explore future opportunities such as rational drug combinations and metabolic intervention. A deeper understanding of the interplay between FGF19 signaling, the tumor microenvironment and systemic metabolism will be essential to unlock its potential for precision oncology.

Keywords:  Cancer therapy; FGF19; FGFR4; Oncogenes; Tumor metabolism

DOI:  https://doi.org/10.7150/thno.121601
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2512936122

Asparagine endopeptidase prompts breast cancer-related pericardial calcification by regulating IGF2 and integrin αvβ5.

Xuefeng Wang, Jian Sun, Bin Lan, Chunyu Wang, Jiayi Ma, Qiaoting Hu, Jun Liu, Haili Cheng, Hong Wen, Jieyu Lin, Xinyi Ren, Huabin Yu, Menghui Jiang, Fangfang Chen, Jiayin Ye, Jingjie Zhai, Haokun Lan, Kai Ouyang, Zihao Jing, Libo Lv, Ying Chen, Weibin Zhuo, Jing Lin, Yu Chen, Jinsong Lu, Yufang Shi, Ying Wang.

  Cardiac calcification, often seen in age-related diseases, impairs heart function, yet its association with malignant tumors remains largely overlooked. Our study revealed that pericardial calcification (PC) occurs in up to 80% of breast cancer patients with pulmonary metastasis. We demonstrate a reciprocal relationship where breast cancer drives PC, which in turn accelerates cancer progression in humans and mice. Lung metastases increase monocyte-derived macrophage and mesenchymal stem cell (MSC)-derived osteoblast infiltration in the pericardial tissue, triggering inflammation and calcification. Mechanistically, metastatic cancer cells in the lungs highly express and secrete asparagine endopeptidase (AEP), which cleaves IGF2BP3 to free IGF2. AEP and IGF2 contribute to PC by promoting osteoblast differentiation in heart tissue through integrin αvβ5 and IGF1R activation, respectively. Pharmacological blockade of integrin αvβ5 and IGF1R, especially when combined, effectively inhibits ectopic osteogenesis and disrupts the feedback loop between PC and cancer progression. These findings elucidate the interplay between metastatic breast cancer and PC and suggest therapeutic strategies to hinder breast cancer progression.

Keywords:  asparagine endopeptidase; breast cancer; insulin-like growth factor; integrin; pericardial calcification

DOI:  https://doi.org/10.1073/pnas.2512936122
Cancer Cell Int. 2025 Dec 05.

PRKCSH deficiency promotes an anti-tumor immune microenvironment via UPR activation and M1 macrophage polarization.

Guo Xiyuan, Worapong Khaodee, Yang Jianghua, Xiaoke Sun, Piyawan Bunpo, Yuan Yulin, Yuan Qing, Ratchada Cressey.

  Lung adenocarcinoma remains one of the most common causes of cancer deaths. The tumor grows by avoiding the immune system and adapting to stress in the endoplasmic reticulum. The IRE1α-XBP1 pathway is a key pathway for cells to sense stress in the endoplasmic reticulum and has a large effect on the immune system. PRKCSH encodes a regulatory subunit of glucosidase II that helps keep the endoplasmic reticulum in balance by modifying how IRE1α works. However, it is unclear how it affects tumor immunity. This study used clinical sample analysis, bioinformatic analysis, CRISPR/Cas9-mediated gene deletion, cytokine profiling, macrophage co-culture, and zebrafish xenograft experiments to investigate the immunological role of PRKCSH. PRKCSH deficiency reduced basal IRE1α phosphorylation but led to exaggerated activation under ER stress, including increased XBP1s and p-JNK signaling. IL-6 and IL-8 secretion was suppressed in PRKCSH-knockout (KO) cancer cells, disrupting cytokine-mediated immune suppression. Conditioned media from PRKCSH-KO cells enhanced M1 macrophage polarization in vitro, as evidenced by increased CD86⁺ macrophages and expression of key M1-polarization markers. These effects were corroborated in zebrafish xenografts, where PRKCSH deficiency diverted the immune environment toward an M1-dominant phenotype. Analysis of clinical pleural effusion samples further validated these findings, revealing a significantly reduced M1/M2 macrophage ratio in malignant versus benign conditions. Furthermore, PRKCSH-KO cells exhibited increased susceptibility to ER stress-induced apoptosis and ferroptosis, along with impaired autophagy. In conclusion, our findings place PRKCSH as a key regulator linking ER stress signaling with tumor immune evasion and cell death pathways. Targeting PRKCSH may represent a promising therapeutic strategy to promote ferroptosis and anti-tumor immunity in lung adenocarcinoma.

Keywords:  ER stress; Glucosidase II beta subunit; IRE1α; Macrophage polarization; PRKCSH; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-025-04104-2
Tissue Cell. 2025 Nov 27. pii: S0040-8166(25)00532-4. [Epub ahead of print]99 103250

Nuclear receptor ERRγ acts as a key transcriptional regulator of hepatic LCN2 expression in CCl4-induced acute liver injury.

Byungyoon Choi, Yoon Seok Jung, Woo-Ram Park, Yong-Hoon Kim, Chul-Ho Lee, Hueng-Sik Choi, Don-Kyu Kim.

  Estrogen-related receptor γ (ERRγ) is a nuclear receptor and transcription factor that plays an important role in liver metabolism by regulating the transcription of genes involved in inflammation, alcohol metabolism, and iron metabolism. Lipocalin 2 (LCN2) is a secreted protein that regulates inflammation, immune response, and iron homeostasis and is involved in liver injury. However, the transcriptional regulation of LCN2 in the liver remains largely unknown. Here, we showed that ERRγ is a critical transcriptional regulator of the hepatic LCN2 gene in carbon tetrachloride (CCl4)-induced acute liver injury. CCl4 treatment significantly increased hepatic ERRγ and LCN2 gene expression by inducing interleukin-6 (IL-6) expression in mice. Interestingly, ERRγ overexpression increased LCN2 gene expression and secretion in the livers of mice. Conversely, mice with the liver-specific knockout of ERRγ (ERRγ-LKO) exhibited significantly decreased CCl4-induced LCN2 gene expression in the liver. Moreover, IL-6 treatment increased LCN2 expression and secretion in the livers of wild-type mice, which was significantly attenuated in ERRγ-LKO mice. Furthermore, deletion and mutation analyses revealed that ERRγ directly binds to ERR-response elements in the LCN2 promoter, modulating LCN2 gene transcription; these data were confirmed by a chromatin immunoprecipitation assay. Finally, administering GSK5182, an inverse agonist of ERRγ, significantly reduced the CCl4-induced levels of LCN2 mRNA and protein in the liver. These findings suggest that ERRγ is a previously unrecognized transcriptional regulator of LCN2 in CCl4-mediated acute liver injury.

Keywords:  Acute liver injury; Carbon tetrachloride; Estrogen-related receptor γ; Interleukin-6; Lipocalin 2

DOI:  https://doi.org/10.1016/j.tice.2025.103250
Aging Cell. 2025 Dec 05. e70307

The Proinflammatory Secretome of Senescent Cells Can Be Controlled by a HIF2A-Dependent Upregulation and a FURIN-Dependent Cleavage of the ANGPTL4 Secreted Factor.

Gabriela Makulyte, Hasan Safwan-Zaiter, Delphine Goehrig, Anda Huna, Adèle Mangelinck, Takumi Mikawa, Alberta Palazzo, Lyvia Moudombi, Jean-Jacques Medard, Marie Chanal, Pacôme Lecot, Marie-Cécile Michallet, Julie Gavard, Serge Adnot, Pierre Dubus, Hiroshi Kondoh, Carl Mann, Nguan Soon Tan, Philippe Bertolino, Jean-Michel Flaman, David Bernard.

  Senescent cells are characterized by a stable proliferation arrest and a senescence-associated secretory phenotype or SASP. Although these cells can have some beneficial effects, including protecting from tumor formation, their accumulation is deleterious during aging as it promotes age-related diseases, including cancer initiation and progression. Although the SASP has a critical role, its composition, regulation and dual role in cancer remain largely misunderstood. Here, we show that ANGPTL4 is one of the rare secreted factors induced in many different types of senescent cells. Importantly, ANGPTL4 knockdown during senescence or its constitutive expression, respectively inhibits or induces classical proinflammatory SASP factors, such as IL1A, IL6 and IL8. The latter effect is mediated upstream of IL1A, an early SASP factor, suggesting an upstream role of ANGPTL4 in SASP induction. This ANGPTL4-dependent proinflammatory SASP can promote human neutrophil activation in ex vivo assays, or tumor initiation in a KRAS-dependent lung tumorigenesis model in mice. This upstream activity of ANGPTL4 in regulating the proinflammatory SASP depends on its upregulation following a hypoxia-like response and HIF2A activation, and its proteolytic processing by the FURIN proprotein convertase. Altogether these findings shed light on a two-step activation of ANGPTL4 by HIF2A and FURIN in senescent cells and its upstream role in promoting the proinflammatory SASP, cancer and potentially other senescence-associated diseases.

Keywords:  ANGPTL4; age‐related diseases; cancer; cellular senescence; inflammation; senescence‐associated secretory phenotype

DOI:  https://doi.org/10.1111/acel.70307
Sci Rep. 2025 Dec 01. 15(1): 42939

Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.

Maureen Yin, Eva M Palsson-McDermott, Órlaith C Henry, Ziqian Ge, Juliana E Toller-Kawahisa, Yukun Min, Anne F McGettrick, Adam L Gordon, Stella B Heffernan, Laura Marrone, Bryan P Marzullo, Katherine L Eales, Sally A Clayton, Daniel A Tennant, Richard K Porter, Luke A J O'Neill.

  Mitochondrial glutathione (mtGSH) supports iron-sulfur cluster (ISC) stability in the electron transport chain (ETC). Here we have investigated the role of the mtGSH transporter SLC25A40 in macrophage activation. SLC25A40 is present in both murine and human macrophages and its expression was increased by LPS treatment. Reducing SLC25A40 expression using siRNA destabilized ISC-rich ETC proteins and elevated mitochondrial and cellular reactive oxygen species (ROS). It also induced expression of the genes Gclc and Gclm, which are involved in GSH biosynthesis. SLC25A40 deficiency also diminished IL-1β and IL-10 production at the transcriptional level in response to LPS. As a result, the production of mature IL-1β was decreased following activation of NLRP3 by nigericin or ATP, with no effect on pyroptosis. Depleting mtGSH with mitochondrially-targeted CDNB phenocopied these defects, whereas supplementation with a cell-permeable GSH ester partially restored pro-IL-1β production. Together, these data identify SLC25A40 as a key regulator that sustains ETC integrity to promote cytokine production, revealing a previously unrecognized role for the SLC25A40-mtGSH axis in coupling mitochondrial redox control to macrophage activation.

Keywords:  Cytokine; Electron transport chain (ETC); Glutathione (GSH); Macrophage immunometabolism; Mitochondria; SLC25A39/40

DOI:  https://doi.org/10.1038/s41598-025-30333-6
Lung Cancer. 2025 Nov 19. pii: S0169-5002(25)00740-8. [Epub ahead of print]211 108848

KRASG12D/G13D-USP15 axis promotes TGF-β/SMAD signaling and glycolytic flux to accelerate NSCLC pathogenesis.

Ikhlas A Sindi, Abdelghafar M Abu-Elsaoud, Amany I Almars, Nahlah M Ghouth, Sameerah Shaheen, Ahmed M Basri, Zaki H Hakami, Tawfiq N Jurayb, Abdullah A Alqasem, Iman S Abumansour, Hind M Naffadi, Nasser A Elhawary, Hassan Rudayni, Mohammed Al-Zharani, Lina M Alneghery, Mohamed M I Ghoneim.

   BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide, with activating KRAS mutations representing a key oncogenic driver. These mutations profoundly reprogram cellular metabolism, especially glycolysis, thereby sustaining uncontrolled tumor proliferation. We identified ubiquitin-specific peptidase 15 (USP15) as a pivotal regulator in KRAS-driven metabolic remodeling and tumor progression. This study aims to elucidate the biological functions and molecular mechanisms of USP15 in KRASG12D/G13D-mutant NSCLC.
METHODS: Comprehensive bioinformatics analyses were performed to identify key metabolic genes significantly associated with NSCLC prognosis. The expression of USP15 was examined in KRAS-mutant NSCLC tissues and cell lines. Functional assays, including CCK-8, EdU incorporation, wound-healing, and subcutaneous xenograft tumor models, were employed to evaluate the oncogenic role of USP15 in vitro and in vivo. In addition, qPCR, Western blotting, ELISA, immunofluorescence, and Seahorse metabolic flux assays were integrated with transcriptomic and metabolomic profiling to comprehensively delineate the mechanisms by which USP15 regulates tumor metabolism and growth in KRASG12D/G13D-mutant NSCLC.
RESULTS: USP15 expression was elevated in KRAS-mutant NSCLC and was transcriptionally regulated by the MEK/ERK signaling pathway. Silencing USP15 significantly inhibited NSCLC cell proliferation, migration, and tumorigenicity, while inducing apoptosis and enhancing chemosensitivity. Multi-omics analyses revealed that USP15 exerts its oncogenic function primarily through modulation of the TGF-β/SMAD signaling axis. Mechanistically, USP15 stabilized SMAD4 by deubiquitination and promoted the phosphorylation of SMAD2/3, thereby sustaining TGF-β/SMAD pathway activation. Moreover, USP15 enhanced glycolytic flux, evidenced by increased extracellular acidification rates and upregulated glycolytic genes expression, ultimately facilitating metabolic adaptation and tumor progression in KRASG12D/G13D-mutant NSCLC.
CONCLUSION: USP15 acts as a critical mediator of oncogenic KRAS-driven metabolic reprogramming in NSCLC by promoting glycolysis via the TGF-β/SMAD signaling cascade. These findings uncover a previously unrecognized role of USP15 in linking metabolic regulation to tumorigenic signaling in KRAS-mutant NSCLC and suggest that targeting USP15 may represent a promising therapeutic strategy for this aggressive cancer subtype.

Keywords:  Glycolysis; KRAS(G12D)(/G13D); Non-small cell lung cancer; TGF-β/SMAD signaling; USP15

DOI:  https://doi.org/10.1016/j.lungcan.2025.108848
Nat Commun. 2025 Dec 04.

Spatiotemporal profiling of modification-specific proteome secretion uncovers an itaconation-activated tyrosine kinase.

Wenjie Lu, Yanling Zhang, Xinrui Ni, Pian Wang, Shentian Zhuang, Wei Qin.

Macrophages secrete diverse signaling proteins critical for intercellular communication and immune responses, processes tightly regulated by post-translational modifications (PTMs). Itaconate, an immunoregulatory metabolite produced in macrophages, induces widespread intracellular protein modification (itaconation), affecting pathways like the KEAP1-NRF2 axis and glycolysis. However, the impact of itaconation on the extracellular proteome and signaling remains poorly characterized. Herein, we introduce PTM-based secretome profiling (PBSP), a novel approach to identify secreted proteins bearing specific PTMs. The method employs a bioorthogonal probe to label modified proteins in live cells, followed by enrichment of labeled proteins from the culture medium upon secretion. We established a streamlined chemoproteomic workflow integrating spintip-based affinity purification (FISAP) with data-independent acquisition (DIA) mass spectrometry for enhanced sensitivity and coverage. This identified 818 macrophage-secreted itaconated proteins, among which 447 are exosome-dependent. Further biochemical analysis revealed that itaconation of Cys239 on FYN (a tyrosine kinase) enhances its kinase activity in macrophages. We finally demonstrate PBSP's versatility by profiling secreted proteins with other PTMs, including fumarate-induced succination. PBSP provides a powerful platform to explore PTM roles in protein secretion, offering insights into PTMs' regulatory functions in cell-cell communication.

DOI: https://doi.org/10.1038/s41467-025-66508-y