bims-meluca 2025-11-30 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–11–30
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake.
Propionate metabolism dysregulation promotes drug-tolerant persister cell survival in non-small cell lung cancer.
GBP2 regulates lung cancer progression through STAT1 and impacts glycolysis.
Serum miRNA Signatures in Cancer Cachexia Depend on Systemic Inflammation.
Association of Immune Cells, Inflammatory Cytokines, and Lung Cancer: A Mediating Mendelian Randomization Study.
New Horizons with Growth Differentiation Factor 15 in Oncology: From Cancer Cachexia and Tumour Immunity to Novel Therapeutic Strategies.
Correlation between F-18 FDG PET/CT-derived metabolic parameters and PD-L1 expression in non-small cell lung cancer patients.
A metabolic-radioimmune signature predicts therapy response and immune reprogramming in non-small cell lung cancer.

bioRxiv. 2025 Oct 22. pii: 2025.10.21.683287. [Epub ahead of print]

JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake.

Ezequiel Dantas, Anirudh Murthy, Jeshua Kim, Tanvir Ahmed, Mujmmail Ahmed, Tiffany Perrier, Shakti Ramsamooj, Isaac Nathoo, Lucas Kniess Debarba, Andre Lima Queiroz, Shiri Li, Baran Ersoy, Miriam Ferrer, Ido Goldstein, Jonathan Gao, Tiffany Lam, Matthew Nagler, Murtaza Malbari, Nasser Altorki, Eduardo Cararo Lopes, Maria Gomez Jenkins, Trishna Das, Mariam Jamal-Hanjani, Eileen White, Tobias Janowitz, Marcus D Goncalves.

Lung cancer is the leading cause of cancer-related death and is frequently accompanied by reduced food intake and cachexia, a debilitating syndrome characterized by weight loss and skeletal muscle wasting. We sought to identify contributors to cachexia using a murine model of lung cancer that reproduces key features of this syndrome. A multiplex cytokine screening approach, integrated with western blot and transcriptomic analyses, identified tumor-derived inflammatory mediators and downstream signaling pathways associated with cachexia. Notably, IL-6 superfamily members were elevated in the tumor and plasma of mice and patients with cachexia. The JAK-STAT3 signaling was upregulated in liver and skeletal muscle, driving the acute phase response and impairing lipid metabolism. Pharmacologic inhibition of JAK1/2 with ruxolitinib improved body weight, fat mass, and overall survival without altering tumor burden. These effects were driven primarily by blunted hypothalamic leptin receptor signaling, which increased food intake early in the disease course. In the liver, JAK inhibition reduced STAT3 activity, restored fatty acid oxidation, and decreased the production of acute-phase proteins. These findings support JAK inhibition as a therapeutic strategy for lung cancer-associated cachexia.

DOI: https://doi.org/10.1101/2025.10.21.683287
bioRxiv. 2025 Oct 15. pii: 2025.10.15.682658. [Epub ahead of print]

Propionate metabolism dysregulation promotes drug-tolerant persister cell survival in non-small cell lung cancer.

Bobak Parang, Liron Yoffe, Rabia Khan, Zhongchi Li, Michal J Nagiec, Eric E Gardner, Yiwey Shieh, Rachel S Heise, Ashish Saxena, Nasser Altorki, John Blenis.

Recent studies show that genetic sequencing can not fully explain drug resistance in non-small cell lung cancer (NSCLC), suggesting undiscovered non-genetic mechanisms that can enable cancer cell survival. Propionate metabolism is the pathway by which odd-chain fatty acids, branched chain amino acids, and cholesterol are metabolized. We have previously shown that methylmalonic acid (MMA), a byproduct of propionate metabolism that accumulates when the pathway is disrupted, can activate epithelial-to-mesenchymal transition (EMT) in cell lines. But the clinical significance of propionate metabolism in cancer patients is not known. Here we show, for the first time, that propionate metabolism is dysregulated in patients with non-small cell lung cancer. MMA is elevated in lung tumors and in the serum of patients with metastatic NSCLC. Metabolism of cobalamin associated B (MMAB), a key regulatory gene of propionate metabolism, is downregulated in NSCLC and drug-tolerant persister cells, leading to MMA accumulation and EMT activation. We show that restoring expression of MMAB in NSCLC enhances targeted therapy and suppresses TGFB signaling. These findings reveal propionate metabolism dysregulation as a non-genetic mechanism of drug resistance and highlight propionate metabolism as a potential therapeutic target.

DOI: https://doi.org/10.1101/2025.10.15.682658
Clin Exp Med. 2025 Nov 25. 26(1): 46

GBP2 regulates lung cancer progression through STAT1 and impacts glycolysis.

Qingbin Xie, Zhongjuan Peng, Dan Gong, Hui Luo.

  Lung cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the need for novel biomarkers and therapeutic targets. In this study, we sought to assess the role of guanylate-binding protein 2 (GBP2) in lung cancer and its potential as a prognostic marker. Immunohistochemical analysis on tissue microarrays revealed significantly elevated GBP2 expression in lung cancer tissues compared to non-neoplastic adjacent tissues, correlating with advanced tumor stages, lymph node metastasis, and poor patient survival. In vitro experiments using GBP2 knockdown in NCI-H1299 and A549 lung cancer cell lines showed reduced cell proliferation, increased apoptosis, and inhibited cell migration, alongside cell cycle arrest at the G2 phase. In vivo studies confirmed that GBP2 knockdown reduces tumor growth in mouse xenograft models. Mechanistically, GBP2 influences lung cancer progression by regulating STAT1, as its knockdown resulted in decreased STAT1 expression. Furthermore, GBP2 was found to modulate glycolytic metabolism in cancer cells, reducing the expression of key glycolytic enzymes and suppressing metabolic activities essential for cancer cell survival and proliferation. In conclusion, GBP2 emerges as a critical factor in lung cancer progression, influencing both cellular proliferation and metabolic processes, and represents a promising therapeutic target.

Keywords:  GBP2; Glycolysis; Lung cancer; STAT1

DOI:  https://doi.org/10.1007/s10238-025-01932-4
Curr Oncol. 2025 Nov 06. pii: 620. [Epub ahead of print]32(11):

Serum miRNA Signatures in Cancer Cachexia Depend on Systemic Inflammation.

Terese Louise Schmidberger Karlsen, Robin Mjelle, Ola Magne Vagnildhaug, Trude Rakel Balstad, Are Korsnes Kristensen, Jens Erik Slagsvold, Ganna S Westwik, Hege Elvebakken, Eva Hofsli, Ingunn Hatlevoll, Tora Skeidsvoll Solheim.

  Cancer cachexia is a complex syndrome marked by involuntary weight and muscle loss, often driven by systemic inflammation. This multicenter, longitudinal observational study investigated circulating microRNA (miRNA) profiles in patients with unresectable locally advanced or metastatic colorectal cancer, comparing those with and without cachexia and inflammation. A total of 168 patients were categorized into four groups based on cachexia and C-reactive protein (CRP) levels. Cachexia was defined using the 2011 consensus criteria, incorporating weight loss, low BMI, and sarcopenia. Patients with both cachexia and systemic inflammation exhibited significantly distinct miRNA profiles as well as poorer overall survival (HR 2.10, p < 0.001) compared to patients with neither condition. No significant differences were observed in patients lacking either cachexia or inflammation or both. Inflammatory cachexia emerged as a biologically distinct entity, with 82 differentially expressed miRNAs. The miR-320-family, miR-6087, miR-4488, miR-29a-3p, miR-194-5p, and miR-10a-5p were most altered, several of which are linked to muscle mass, metabolism, lipid, and protein synthesis. These findings highlight the pivotal role of systemic inflammation in cancer cachexia and support its inclusion in diagnostic criteria. Moreover, circulating miRNAs may serve as promising biomarkers for identifying cachexia in cancer patients.

Keywords:  MiRNA; biomarkers; cachexia; cancer; colorectal cancer; inflammation

DOI:  https://doi.org/10.3390/curroncol32110620
Mediators Inflamm. 2025 ;2025 3834641

Association of Immune Cells, Inflammatory Cytokines, and Lung Cancer: A Mediating Mendelian Randomization Study.

Lang Li, Ying Zhu, Chenchong Zhao, Yinuo Tangwu, Lvyuan He, Gaochen Lan.

   Background: Lung cancer oncogenesis involves interactions between immune cells and inflammatory cytokines. However, their causal relationships and mediating mechanism remain unclear.
Methods: Using a mediating Mendelian randomization (MR) approach, we analyzed genome-wide association study (GWAS) data for 731 immune-cellular phenotypes, 41 cytokines, and eight related lung cancer phenotypes.
Results: BAFF-R expression in IgD+ CD24+ B cells was positively associated with lung adenocarcinoma (LUAD) risk (odds ratio [OR], 1.0168 [95% confidence interval [CI], 1.0006-1.0332]), mediated by macrophage migration inhibition factor (MIF) with a mediation proportion of 14.2% (95% CI, 0.00007-0.0046). CD39 expression on secreting CD4 Tregs was related to an increased risk of small-cell lung cancer (SCLC) (OR, 1.0306 [95% CI, 1.0006-1.0616]), mediated by interleukin (IL)-2 and IL-6 with mediation proportions of 8.43% (95% CI, 0.00005-0.005) and 5.1% (95% CI, 0.00006-0.003), respectively. CD28 expression on CD39+ CD4+ T cells was positively correlated to lung squamous cell carcinoma (LUSC) risk (OR, 1.0335 [95% CI, 1.009-1.0586]), inversely mediated by IL-16 (95% CI, -0.01 to -0.0003).
Conclusions: These findings reveal the associations between immune cells, inflammatory cytokines, and lung cancer risk, providing insights into cancer diagnosis and treatment.

Keywords:  causal relationship; immune cell; inflammatory cytokine; lung cancer; mendelian randomization

DOI:  https://doi.org/10.1155/mi/3834641
Curr Oncol. 2025 Oct 29. pii: 604. [Epub ahead of print]32(11):

New Horizons with Growth Differentiation Factor 15 in Oncology: From Cancer Cachexia and Tumour Immunity to Novel Therapeutic Strategies.

Keiji Sugiyama, Naureen Starling, Ian Chau.

  Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine produced by tumour cells and peripheral cells. It is implicated in the development of cancer cachexia, a debilitating condition for which no effective pharmacological therapy currently exists. GDF-15 regulates appetite and metabolic processes through complex neural and hormonal networks. Furthermore, it has been implicated in chemotherapy-induced nausea and vomiting, representing a potential therapeutic target. GDF-15 negatively affects tumour immunity, suggesting that anti-GDF-15 therapy could potentially enhance immune responses and help overcome resistance to immunotherapy. Recently, early clinical trials have reported preliminary results of GDF-15-targeted therapies in alleviating cancer cachexia and potentially enhancing the efficacy of immunotherapy. This review aims to provide an overview of the role of GDF-15 in cancer cachexia, including the underlying neural mechanisms and their involvement in tumour immunity. This review also summarises recent clinical trial findings and discusses future perspectives on GDF-15-targeted therapy in oncology, offering important insights for future research.

Keywords:  autonomic nervous system; cancer cachexia; growth differentiation factor 15; immune checkpoint inhibitors

DOI:  https://doi.org/10.3390/curroncol32110604
Rev Esp Med Nucl Imagen Mol (Engl Ed). 2025 Nov 26. pii: S2253-8089(25)00163-6. [Epub ahead of print] 500258

Correlation between F-18 FDG PET/CT-derived metabolic parameters and PD-L1 expression in non-small cell lung cancer patients.

S Kesim, F Ozulker, G Gul Gecmen, N Turan.

   OBJECTIVES: Programmed death-ligand 1 (PD-L1) expression serves as a critical biomarker for selecting patients eligible for treatment with immune checkpoint inhibitors. Herein, we investigated the association between PD-L1 expression and various FDG PET/CT-derived metabolic parameters in patients with non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: This retrospective study included 81 NSCLC patients who underwent pre-treatment F-18 FDG PET/CT imaging and histopathological evaluation of PD-L1 expression. PD-L1 tumour proportion score (TPS) was determined using the SP263 immunohistochemical assay. PD-L1 positivity was defined as TPS ≥ 1%. Quantitative PET/CT parameters-SUVmax, SUVmean, SULpeak, SULmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and heterogeneity indices (coefficient of variation [COV] and SUV-based heterogeneity index [HI])-were analyzed in relation to PD-L1 TPS.
RESULTS: PD-L1 positivity was identified in 30 patients (37%). Although SUVmax, SUVmean, SULpeak, and SULmax values tended to be higher in PD-L1-positive patients, these differences were not statistically significant. Conversely, MTV and TLG were higher in the PD-L1-negative group. Among all parameters, HI was significantly elevated in the PD-L1-positive group (p = 0.031), and remained significant across PD-L1 expression strata (p = 0.037). In metastatic patients, HI and COV showed significant positive correlation with PD-L1 expression (r = 0.34 and 0.33, respectively). ROC analysis identified a HI cut-off of 1.59 to predict PD-L1 positivity with 90% sensitivity and 50% specificity (AUC = 0.674).
CONCLUSIONS: Tumor heterogeneity indices, particularly HI and COV derived from FDG PET/CT, demonstrated stronger predictive value for PD-L1 expression than conventional metabolic parameters. These findings suggest that metabolic heterogeneity may serve as a useful noninvasive imaging biomarker for guiding immunotherapy in NSCLC.

Keywords:  CPNM; FDG PET/CT; Heterogeneidad tumoral; Ligando 1 de muerte programada (PD-L1); NSCLC; PET/TC con FDG; Programmed death-ligand 1; Tumor heterogeneity

DOI:  https://doi.org/10.1016/j.remnie.2025.500258
Front Oncol. 2025 ;15 1693277

A metabolic-radioimmune signature predicts therapy response and immune reprogramming in non-small cell lung cancer.

Zihong Zhu, Yichen Zan, Mengqian Jiang, Ran Zhang, Dawei Chen, Guanglu Dong.

   Objective: This study systematically investigates radiotherapy-induced metabolic remodeling across the TME, encompassing tumor cells, immune cells, and tumor-draining lymph nodes (TDLNs), and establishes a prognostic signature based on radioresistance-related metabolic genes (RRMGs) to optimize therapeutic stratification and radiosensitizer discovery.
Methods: Bulk transcriptomic datasets of NSCLC tumor cells and tumor-draining TDLNs were systematically integrated, along with single-cell RNA-seq data from tumor tissues, to reconstruct metabolic flux maps using the single-cell Flux Estimation Analysis (scFEA) algorithm. WGCNA and Cox regression modeling of TCGA radiotherapy cohort were used to identify core RRMGs. A prognostic nomogram was developed using risk scores derived from these genes, while CIBERSORT and TIDE algorithms were used to evaluated TIME features and immunotherapy responses. Candidate radiosensitizing agents were predicted via the oncoPredict platform and validated by molecular docking, qRT-PCR and western blotting in radioresistant NSCLC cells.
Results: Radiotherapy induced profound metabolic heterogeneity across the NSCLC TIME: Tumor cells and draining TDLNs exhibited suppressed tricarboxylic acid (TCA) cycle activity and N-glycan biosynthesis, while immune cells displayed upregulated serine metabolism alongside divergent shifts in lymphoid subsets. Seven RRMGs were identified as key prognostic determinants, including PGD, IDH2, G6PD, ALDH3A1, UPP1, XYLT2, AACS. The RRMG-based risk model robustly predicted poor overall survival (HR = 4.726, 95% CI: 2.154-10.371; P<0.001), with high predictive accuracy (AUC for 1-, 3-, and 5-year: 0.752, 0.778, and 0.879). High-risk patients demonstrated an immunosuppressive TIME marked by elevated tumor-promoting immune cell infiltration and TIDE scores. The model's generalizability was verified in an independent radioimmunotherapy cohort (AUC: 0.618). Experimental validation revealed significant upregulation of high-risk RRMGs in radioresistant NSCLC cells. Ouabain and two novel compounds (BRD-K28456706, BRD-K42260513) were nominated as promising radiosensitizers.
Conclusion: Radiotherapy-induced metabolic reprogramming in TIME drives resistance of NSCLC. The RRMG signature predicts radioimmunotherapy outcomes for patient stratification. Identifying ouabain and novel compounds highlights targeting metabolic vulnerabilities as a translatable strategy to overcome resistance.

Keywords:  metabolic reprogramming; non-small cell lung cancer; radioresistance; radioresistance-related metabolic genes; tumorimmune microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1693277