bims-meluca 2025-11-16 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–11–16
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Do Inflammatory and Nutritional Markers Predict Prognosis in Metastatic Non-Small Cell Lung Cancer Patients Receiving Nivolumab.
Non-targeted metabolomics reveals diagnostic biomarker in the plasma of patients with lung cancer.
Effects of small extracellular vesicles isolated from pleural effusion on lung cancer cell proliferation and migration.
Advancements of investigational agents for cancer cachexia: what clinical progress have we seen in the last 5 years?
Targeting polyamine metabolism and ferroptosis enhances the efficacy of KRAS-targeted therapy depending on KEAP1 status.
Identification and validation of an immune-related programmed cell death signature for predicting prognosis and immunotherapy in large-scale multicenter cohorts for lung adenocarcinoma.
Integrative analysis of fatty acid metabolism and identification of ANLN as a novel prognostic marker in lung adenocarcinoma.

J Inflamm Res. 2025 ;18 15283-15292

Do Inflammatory and Nutritional Markers Predict Prognosis in Metastatic Non-Small Cell Lung Cancer Patients Receiving Nivolumab.

Esra Zeynelgil, Dilek Çağlayan, Selahattin Çelik, Hatice Ayyıldız Sevim, Hayriye Şahinli, Serdar Karakaya, Tülay Eren.

   Objective: To investigate the prognostic value of clinical and inflammatory markers predicting response to nivolumab in patients with metastatic non-small cell lung cancer (NSCLC).
Materials and Methods: Clinical, demographic and laboratory data of stage 4 NSCLC patients who were treated between February 2021 and November 2024 were analyzed. Before nivolumab treatment, inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), prognostic nutritional index (PNI), hemoglobin-albumin-lymphocyte-platelet score (HALP), neutrophil-to-eosinophil ratio (NER) and C-reactive protein-to-albumin ratio (CAR) were calculated. Factors affecting overall survival (OS) were determined by Cox regression analysis, and ROC curve analysis was used to calculate the ideal cut-off.
Results: The study included 229 NSCLC patients and the median age of the patients was 63 years. The majority were male (84.3%) and had right lung localization (56.8%). Median overall survival was calculated as 21.2 months (95% CI: 17.4-25.0). In univariate cox-regression analysis, the presence of brain metastases (HR: 2.08; p=0.004), liver metastases (HR: 1.85; p=0.014) and adrenal metastases (HR: 1.64; p=0.045) negatively affected the treatment response. Inflammatory markers such as high NLR (HR: 2.04; p<0.001), high SII (HR: 1.96; p<0.001), high CAR (HR: 1.84; p=0.001), high PLR (HR: 1.60; p=0.009) and high SIRI (HR: 1.51; p=0.021), low PNI (HR: 0.48; p<0.001), low HALP (HR: 0.49; p<0.001) and low LMR (HR: 0.65; p=0.016) were associated with poor prognosis. In multivariate analysis, the presence of brain metastasis (HR: 2.84; p<0.001), adrenal metastasis (HR: 1.64; p=0.046) and low PNI (HR: 0.44; p<0.001) together predicted poor prognosis and formed a statistical model on treatment response.
Conclusion: In patients with metastatic NSCLC, nivolumab treatment response is predicted by inflammatory markers and the presence of brain and adrenal metastases. It was concluded that low PNI among inflammatory markers is a strong prognostic indicator in this patient group.

Keywords:  immune checkpoint inhibitors; overall survival; prognostic nutritional index; systemic inflammation index

DOI:  https://doi.org/10.2147/JIR.S541842
Oncol Lett. 2026 Jan;31(1): 16

Non-targeted metabolomics reveals diagnostic biomarker in the plasma of patients with lung cancer.

Yan Liu, Yangmin Li, Haijun Hou, Yanyan Dong, Haitong Tian, Yanan Zhao, Ke Li, Jiayuan Zhou, Fujie Song, Yan Li.

  Lung cancers are malignant tumors with high incidence and mortality rates and a 5-year survival rate that depends on the stage at the time of diagnosis. Screening methods for lung cancer are becoming increasingly diverse, but existing approaches lack sensitivity or specificity for early lesions, posing notable challenges for the early diagnosis of lung cancer. Therefore, it is essential to explore potential biomarkers with high sensitivity and specificity to achieve early diagnosis. The present study employed liquid chromatography-mass spectrometry to analyze plasma metabolic changes in patients with lung cancer or pulmonary nodules and in healthy individuals. By combining quantitative and qualitative methods, differential metabolites were identified and the performance of these metabolites was evaluated using receiver operating characteristic curve analyses to screen for potential biomarkers. A total of 50 differential metabolites, six of which had an area under the curve of >0.9, were identified among the three groups and regarded as potential biomarkers for distinguishing between lung cancer, pulmonary nodules and healthy individuals, as well as between lung cancer and pulmonary nodules. In addition, metabolic pathways were screened using the Kyoto Encyclopedia of Genes and Genomes databases. The results demonstrated that significant changes were observed in the metabolism of substances including linoleic acid, α-linolenic acid, arginine and proline, suggesting that the development of lung cancer may be associated with alterations in amino acid and lipid metabolism. In conclusion, the present findings provided potential biomarkers to differentiate between lung cancer, pulmonary nodules and healthy individuals, offering insights into the pathological mechanisms of lung cancer.

Keywords:  diagnostic biomarker; liquid chromatography-mass spectrometry; lung cancer; metabolomics; plasma metabolic biomarker

DOI:  https://doi.org/10.3892/ol.2025.15369
Hum Cell. 2025 Nov 15. 39(1): 10

Effects of small extracellular vesicles isolated from pleural effusion on lung cancer cell proliferation and migration.

G Cammarata, A Masucci, I Giusti, V Dolo, C Di Sano, S Taverna, E Pace.

  Pleural effusion (PE) is a common clinical manifestation associated with advanced stages of both malignant and non-malignant diseases. PE frequently occurs in advanced non-small cell lung cancer (NSCLC) and contributes to tumor progression. NSCLC accounts for more than 85% of the lung cancers and remains a problem worldwide due to its late diagnosis and low rate of response to treatment. Extracellular vesicles (EVs) present in PE are emerging as key mediators of intercellular communication, capable of transferring oncogenic signals through their molecular cargo. Among these molecules, microRNAs (miRNAs) are increasingly recognized as important drivers of cancer progression. miR-21 is a representative onco-miRNA, involved in lung cancer progression; moreover EV-miR-21 upregulation at the pre-dissemination stage promotes cancer cell survival in the pleural cavity. This study compares, for the first time, the functional role of EVs isolated from malignant PE in NSCLC patients (NSCLC-PE-EVs) with those isolated from PE in patients with congestive heart failure (CHF-PE-EVs), focusing on their ability to modulate lung cancer cell behavior. The effects of these EVs were evaluated on COLO699 lung adenocarcinoma cells with proliferation, migration, and gene expression assays. NSCLC-PE was found to contain approximately twice the amount of EVs compared to CHF-PE. NSCLC-PE-EVs were enriched in the oncogenic miR-21-5p, while CHF-PE-EVs had higher levels of the tumor-suppressive miR-126-3p. Only NSCLC-PE-EVs induced dose-dependent increases in COLO699 cell proliferation and migration, consistent with elevated miR-21-5p expression. Functional studies confirmed that miR-21-5p mediates these effects by downregulating PTEN and PDCD4, and by upregulating MMP9 expression. Our findings show that NSCLC-PE-EVs promote malignant phenotypes in lung cancer cells via the transfer of miR-21-5p.

Keywords:  Congestive heart failure; Extracellular vesicles; MiR-21-5p; Non-Small cell lung cancer; Pleural effusion

DOI:  https://doi.org/10.1007/s13577-025-01322-8
Expert Opin Investig Drugs. 2025 Nov 12. 1-13

Advancements of investigational agents for cancer cachexia: what clinical progress have we seen in the last 5 years?

Maurizio Muscaritoli, Alessio Molfino, Simona Orlando, Federica Tambaro.

   INTRODUCTION: Cancer cachexia is a multifactorial syndrome affecting up to 80% of advanced cancer patients, associated with poor quality of life, increased cancer-treatment toxicity, and reduced survival. Despite its clinical burden, no FDA- or EMA-approved pharmacologic therapies currently exist.
AREAS COVERED: This review covers key investigational therapies developed over the past five years, with a focus on agents targeting Growth Differentiation Factor 15 (GDF-15), including ponsegromab, AV-380, and NGM120. Additional agents include ghrelin receptor agonists (e.g. anamorelin), anabolic/catabolic modulators (ACM-001), and cannabinoids (ART27.13). The evolving role of low-dose olanzapine is also discussed in the 2023 ASCO guideline update. Advancements in early detection, including AI-driven biomarker models and the use of circulating miRNAs, are discussed.
EXPERT OPINION: Targeting GDF-15 represents a paradigm shift in cancer cachexia treatment, with ponsegromab leading the pipeline and entering Phase 3 trials. Anamorelin has demonstrated clinical utility in improving appetite and body weight. Despite recent progress, cancer cachexia undoubtedly represents a still clinically unmet need in everyday routine praxis. The lack of standardized endpoints, heterogeneity of the syndrome, and absence of FDA-approved treatments remain major barriers to treatment implementation. Multimodal strategies combining pharmacological treatment with nutritional and rehabilitative support are likely to define future therapeutic success.

Keywords:  Cancer cachexia; GDF-15 inhibition; anamorelin; ghrelin receptor agonist; multimodal therapy; ponsegromab

DOI:  https://doi.org/10.1080/13543784.2025.2588640
Nat Commun. 2025 Nov 11. 16(1): 9923

Targeting polyamine metabolism and ferroptosis enhances the efficacy of KRAS-targeted therapy depending on KEAP1 status.

Yunyi Bian, Guangyao Shan, Guoshu Bi, Zhijie Xu, Jiaqi Liang, Yuanliang Yan, Wei Guo, Qihai Sui, Yanjun Yi, Haochun Shi, Tao Lu, Huan Zhang, Qun Wang, Hong Fan, Wei Jiang, Cheng Zhan.

The resistance to KRAS-targeted therapies, particularly due to co-occurring gene mutations, remains a significant challenge. Through a metabolite library screening, we reveal that polyamines sensitize KRAS inhibitors only in KRASMU/KEAP1WT cells but not in KRASMU/KEAP1MU cells. Transcriptome sequencing and metabolome profiling pinpoint SAT1, the key enzyme in polyamine metabolism, as essential for this divergence. In KRASMU/KEAP1WT context, treatment of KRAS inhibitors activates JNK/c-Jun pathway and SAT1 expression, while the augmented SAT1 facilitates polyamine metabolism and KRAS inhibitors-induced ferroptosis. Conversely, in KRASMU/KEAP1MU cells, activated JNK promotes the degradation of NRF2, thereby inhibiting SAT1 expression. Our results further demonstrate that polyamine supplementation enhances KRAS-targeted therapy in KRASMU/KEAP1WT resistant cells, patient-derived organoids, xenografts, and spontaneously tumorigenic mice, while KRASMU/KEAP1MU models require lentivirus or adeno-associated virus-mediated SAT1 overexpression prior to polyamine treatment, to augment ferroptosis and drug sensitivity. Our findings highlight SAT1-mediated polyamine metabolism as a promising target in precision treatments for KRAS-mutant cancers.

DOI: https://doi.org/10.1038/s41467-025-65441-4
Transl Cancer Res. 2025 Oct 31. 14(10): 6152-6171

Identification and validation of an immune-related programmed cell death signature for predicting prognosis and immunotherapy in large-scale multicenter cohorts for lung adenocarcinoma.

Zhetao Li, Chuyun Fu, Jie Chen, Wenbo Ji, Zaiqi Ma.

   Background: Lung adenocarcinoma (LUAD) is a major subtype of lung cancer with a 5-year survival rate of less than 20%. While immunotherapy has revolutionized cancer treatment, only 10-20% of cases show durable responses to immune checkpoint blockade. Thus, developing accurate methods to predict prognosis and response to immune checkpoint inhibitors (ICIs) is crucial. Programmed cell death (PCD) plays a significant role in maintaining tissue homeostasis and responding to various physiological or pathological conditions. Increasing evidence suggests that PCD is involved in tumor initiation, development, prognosis, and response to immunotherapy. To provide reliable LUAD clinical tools, we developed an immune-related programmed cell death signature (IRPCDS) and validated its ability to predict prognosis and ICI response for precision medicine.
Methods: In this study, we integrated 18 PCD signatures to develop an IRPCDS. We employed 10 machine learning algorithms and 101 algorithm combinations to assess the performance of the IRPCDS. The signature was validated across multiple cohorts to ensure its robustness in predicting clinical outcomes for LUAD patients.
Results: The IRPCDS demonstrated strong performance in predicting the clinical prognosis of LUAD patients, effectively stratifying them into different risk groups for targeted interventions. Notably, the IRPCDS outperformed traditional clinicopathological factors and previously published 52 signatures in predicting overall survival (OS). Patients classified in the low-risk group exhibited high levels of immune infiltration and favorable responses to ICIs, while those in the high-risk group showed a higher overall mutation burden and an increased frequency of mutations in driver genes associated with LUAD. Additionally, we validated the expression of the IRPCDS genes at both the transcriptional and protein levels across multiple datasets and clinical specimens.
Conclusions: The IRPCDS serves as a robust and promising tool for enhancing clinical outcomes and precision medicine for individual LUAD patients. By integrating PCD signatures, this approach provides valuable insights into the prognostic landscape of LUAD, paving the way for more effective immunotherapeutic strategies.

Keywords:  Lung adenocarcinoma (LUAD); immunotherapy response; machine learning; prognostic model; programmed cell death (PCD)

DOI:  https://doi.org/10.21037/tcr-2025-1015
J Thorac Dis. 2025 Oct 31. 17(10): 7937-7954

Integrative analysis of fatty acid metabolism and identification of ANLN as a novel prognostic marker in lung adenocarcinoma.

Fangfang Yang, Peng Jiang, Xingfa Huo, Xiao Xu, Na Zhou, Xiaochun Zhang.

   Background: Dysregulation of fatty acid (FA) metabolism represents a critical contribution to the tumorigenesis and progression of lung adenocarcinoma (LUAD). This study aimed to identify the roles of FA metabolism and search for potential therapeutic targets.
Methods: The genomic and clinical data from The Cancer Genome Atlas (TCGA)-LUAD cohort underwent univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses to establish a FA metabolism-related gene (FAMG) signature. Immunotherapy efficacy was evaluated via the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Pharmacological sensitivity to conventional chemotherapeutic agents and molecular targeted therapies was evaluated using the "pRRophetic" R package. Through integrative multi-omics analysis, ANLN was identified as a key gene with significant prognostic value. Gene silencing via small interfering RNA (siRNA) transfection was employed for functional validation. We further analyzed the biological role and mechanism of ANLN through bioinformatics and experimental analyses in LUAD cell lines.
Results: The FAMG prognostic signature indicated clinical utility in predicting patient outcomes and stratifying survival probabilities. The signature showed predictive capacity for therapeutic responses across immunotherapy, chemotherapy, and targeted drugs, supporting precision oncology applications. Experimental validation confirmed that ANLN knockdown significantly attenuated malignant phenotypes through impairing cellular proliferation and migration, enhancing apoptotic induction in LUAD. Mechanistically, we discovered for the first time that ANLN knockdown inhibited FA synthesis, glycolysis, and epithelial-mesenchymal transition (EMT) by downregulating the AKT/mTOR/HIF-1α signaling axis, representing a novel regulatory mechanism in LUAD metabolism.
Conclusions: This work delineates FA metabolic heterogeneity and its predictive function of personalized treatment in LUAD. ANLN is established as both a prognostic biomarker and metabolic regulator through modulation of the AKT/mTOR/HIF-1α signaling axis. Our findings provide a framework for developing metabolism-targeted treatment strategies.

Keywords:  AKT/mTOR/HIF-1α pathway; ANLN; Lung adenocarcinoma (LUAD); fatty acid metabolism (FA metabolism); prognosis

DOI:  https://doi.org/10.21037/jtd-2025-836