bims-meluca 2025-04-27 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–04–27
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
Metagenomics and Non-Targeted Metabolomics Reveal the Role of Gut Microbiota and Its Metabolites in Brain Metastasis of Non-Small Cell Lung Cancer.
Analysis of clinical factors and inflammatory cytokines in patients with lung cancer and sarcopenia: a prospective single-center cohort study.
In vivo functional screens reveal KEAP1 loss as a driver of chemoresistance in small cell lung cancer.
Glucose sensing and the unfolded protein response.
Endoplasmic reticulum stress related super-enhancers suppress cuproptosis via glycolysis reprogramming in lung adenocarcinoma.
Identification and Validation of Amino Acid Metabolism-Related Biomarkers and Investigation of their Potential Mechanisms in Lung Adenocarcinoma.
Downregulation of GFPT2 enhances cisplatin chemotherapy sensitivity in STK11/KRAS mutant non-small cell lung cancer by regulating the hexosamine biosynthesis pathway, resisting tumor growth.

Nat Metab. 2025 Apr;7(4): 823-841

Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.

Ying Liu, Ezequiel Dantas, Miriam Ferrer, Ting Miao, Mujeeb Qadiri, Yifang Liu, Aram Comjean, Emma E Davidson, Tiffany Perrier, Tanvir Ahmed, Yanhui Hu, Marcus D Goncalves, Tobias Janowitz, Norbert Perrimon.

Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.

DOI: https://doi.org/10.1038/s42255-025-01265-2
Thorac Cancer. 2025 Apr;16(8): e70068

Metagenomics and Non-Targeted Metabolomics Reveal the Role of Gut Microbiota and Its Metabolites in Brain Metastasis of Non-Small Cell Lung Cancer.

Chen-Guang Liu, Mei-Xi Lin, Yu Xin, Man Sun, Jia Cui, Dan Liu, Dan Zang, Jun Chen.

   BACKGROUND: Brain metastasis is a common and severe complication in non-small cell lung cancer (NSCLC) patients, significantly affecting prognosis. However, the role of gut microbiota and its metabolites in NSCLC brain metastasis remains poorly understood. This study aims to explore the relationship between gut microbiota, metabolites, and the development of brain metastasis in NSCLC.
METHODS: We conducted an integrative analysis combining metagenomics and non-targeted metabolomics on baseline fecal samples from NSCLC patients with brain metastasis (n = 18) and those without distant metastasis (n = 12). Gut microbiota composition and metabolite profiles were detected and analyzed, and statistical methods, including machine learning models, were applied to identify differences and potential biomarkers.
RESULTS: Significant differences in gut microbiota composition were found between the two groups, with higher microbial diversity observed in patients with brain metastasis. Specific genera, such as Paenibacillus, Fournierella, and Adlercreutzia, were enriched in the brain metastasis group. Metabolomic analysis revealed altered levels of short-chain fatty acids and other metabolites associated with immune modulation and vascular permeability, including angiotensin (1-7). These changes were linked to the metastatic process and may influence brain metastasis development. Furthermore, machine learning models identified key biomarkers, such as Raoultibacter, Mobilibacterium, and N-acetyl-L-glutamic acid, which could serve as valuable indicators for brain metastasis.
CONCLUSIONS: Our findings suggest that gut microbiota dysbiosis and its metabolic products may contribute to the development of brain metastasis in NSCLC. The identification of microbiota-derived biomarkers holds potential for early detection and therapeutic intervention in NSCLC brain metastasis.

Keywords:  brain metastasis; gut microbiota; metabolomics; metagenomics; non‐small cell lung cancer

DOI:  https://doi.org/10.1111/1759-7714.70068
Front Oncol. 2025 ;15 1564399

Analysis of clinical factors and inflammatory cytokines in patients with lung cancer and sarcopenia: a prospective single-center cohort study.

Yalan Liu, Hui Zhang, Peng Chen, Xinfu Liu.

   Objective: To analyze the relationship between the expression of various clinical factors, inflammatory cytokines, and sarcopenia and provide new ideas for whole-course management and curative effect prediction in patients with lung cancer and sarcopenia.
Methods: A total of 135 patients with lung cancer recruited in the Department of Oncology, Central Hospital of Shaoyang, from January 2022 to January 2024 were analyzed and divided into sarcopenia (75 cases) and non-sarcopenia (60 cases) groups. Various statistical analyses methods were used to analyze the correlation between 4 kinds of inflammatory cytokines and sarcopenia in patients with lung cancer.
Results: In this study, 55.6% (75/135) of the lung cancer patients were found to have sarcopenia, with a median age of 67.3 years. Those with sarcopenia were found to be significantly associated with increased age, long duration of cigarette inhalation, and high risk of malnutrition. The results of the regression analysis indicated that long-term cigarette inhalation (odds ratio [OR]=8.187), body mass index (BMI; OR=1.356), and Nutritional Risk Screening 2002 score (OR=0.050) were statistically significant (P<0.05). Multivariable logistic regression analysis indicated that patients in the sarcopenia group were positively correlated with interleukin (IL)-6 and tumour necrosis factor (TNF)-α (P<0.05). The progression-free and overall survival of lung cancer patients with sarcopenia who received chemotherapy were significantly increased compared to those who did not receive chemotherapy(P<0.05).
Conclusions: Patients with a long-term cigarette inhalation, high risk of malnutrition, and low BMI have a higher probability of sarcopenia. The increased expression levels of IL-6 are positively correlated with the occurrence of sarcopenia, as well as TNF-α. The intervention of chemotherapy affects inflammatory cytokine levels. Early chemotherapy may extend the survival time of patients with lung cancer and sarcopenia.

Keywords:  cytokines; lung cancer; malnutrition; prognosis; sarcopenia

DOI:  https://doi.org/10.3389/fonc.2025.1564399
Sci Adv. 2025 Apr 25. 11(17): eadq7084

In vivo functional screens reveal KEAP1 loss as a driver of chemoresistance in small cell lung cancer.

Lauren Brumage, Scott Best, Daniel S Hippe, Eli Grunblatt, Pritha Chanana, Feinan Wu, Myung Chang Lee, Zhe Ying, Ali Ibrahim, Jae Heun Chung, Anna Vigil, Jackson Fatherree, Slobodan Beronja, Patrick Paddison, Lucas Sullivan, Barzin Nabet, David MacPherson.

Exquisitely chemosensitive initially, small cell lung cancer (SCLC) exhibits dismal outcomes owing to rapid transition to chemoresistance. Elucidating the genetic underpinnings has been challenging owing to limitations with cellular models. As SCLC patient-derived xenograft (PDX) models mimic therapeutic responses, we perform genetic screens in chemosensitive PDX models to identify drivers of chemoresistance. cDNA overexpression screens identify MYC, MYCN, and MYCL, while CRISPR deletion screens identify KEAP1 loss as driving chemoresistance. Deletion of KEAP1 switched a chemosensitive SCLC PDX model to become chemoresistant and resulted in sensitivity to inhibition of glutamine metabolism. Data from the IMpower133 clinical trial revealed ~6% of patients with extensive-stage SCLC exhibit KEAP1 genetic alterations, with activation of a KEAP1/NRF2 transcriptional signature associated with reduced survival upon chemotherapy treatment. While roles for KEAP1/NRF2 have been unappreciated in SCLC, our genetic screens revealed KEAP1 loss as a driver of chemoresistance, while patient genomic analyses demonstrate clinical importance.

DOI: https://doi.org/10.1126/sciadv.adq7084
FEBS J. 2025 Apr 24.

Glucose sensing and the unfolded protein response.

Mabel Cruz-Rodríguez, Eric Chevet, Cristina Muñoz-Pinedo.

  The unfolded protein response (UPR) is activated primarily upon alteration of protein folding in the endoplasmic reticulum (ER). This occurs under physiological situations that cause an abrupt increase in protein synthesis, or under redox and metabolic stresses. Among the latter, hyperglycemia and glucose scarcity have been identified as major modulators of UPR signaling. Indeed, the first mammalian UPR effector, the glucose-regulated protein 78, also known as BiP, was identified in response to glucose deprivation. Tunicamycin, arguably the most commonly used drug to induce ER stress responses in vitro and in vivo, is an inhibitor of N-glycosylation. We compile here evidence that the UPR is activated upon physiological and pathological conditions that alter glucose levels and that this is mostly mediated by alterations of protein N-glycosylation, ATP levels, or redox balance. The three branches of the UPR transduced by PERK/ATF4, IRE1/XBP1s, and ATF6, as well as non-canonical ER sensors such as SCAP/SREBP, sense ER protein glycosylation status driven by glucose and other glucose-derived metabolites. The outcomes of UPR activation range from restoring protein N-glycosylation and protein folding flux to stimulating autophagy, organelle recycling, and mitochondrial respiration, and in some cases, cell death. Anabolic responses to glucose levels are also stimulated by glucose through components of the UPR. Therefore, the UPR should be further studied as a potential biomarker and mediator of glucose-associated diseases.

Keywords:  ATF6; IRE1; PERK; glucose; glycosylation; nutrient sensing; starvation; unfolded protein response

DOI:  https://doi.org/10.1111/febs.70113
Cell Death Dis. 2025 Apr 19. 16(1): 316

Endoplasmic reticulum stress related super-enhancers suppress cuproptosis via glycolysis reprogramming in lung adenocarcinoma.

Yan Gu, Hongchang Wang, Wentao Xue, Linjia Zhu, Chenghao Fu, Wenhao Zhang, Guang Mu, Yang Xia, Ke Wei, Jun Wang.

The role of copper in tumor progression is thought to be a double-edged sword. Moderate levels of copper promote tumor progression, while excess copper induces a novel form of programmed cell death known as cuproptosis. However, the relationship between lung adenocarcinoma (LUAD) and cuproptosis remains poorly understood. Copper colorimetric assay identified the progression of LUAD simultaneous associated with higher copper accumulation. Single-cell RNA sequencing further identified the activation of unfolded protein response correlates with copper accumulation, particularly the spliced form of XBP1 (XBP1s). XBP1s negatively regulates the protein level of LIPT1 to inhibit LUAD cell death induced by copper-loaded ionophore elesclomol. CUT&Tag-seq and chromosome conformation capture (3 C) experiment showed that XBP1s affect the frequency of MGRN1 promoter-enhancer interactions in various copper environments by forming super-enhancers. Additionally, MGRN1 promotes the ubiquitination and degradation of LIPT1, which in turn supports glycolysis in LUAD cells. In mouse xenograft models, overexpression of XBP1s significantly inhibits the cuproptosis induced by copper ionophores. Co-administration with SEs inhibitor and copper ionophore also markedly reduced tumor volume and growth rate. Our study sheds light on the molecular mechanism by which XBP1s affect the cuproptosis through super-enhancers formation in LUAD and suggested the potential clinical value of copper ionophore as well as a potential biomarker XBP1s for treatment response.

DOI: https://doi.org/10.1038/s41419-025-07613-0
Curr Gene Ther. 2025 Apr 18.

Identification and Validation of Amino Acid Metabolism-Related Biomarkers and Investigation of their Potential Mechanisms in Lung Adenocarcinoma.

Xu Zhu, Ying Zhang, Peiying Pan, Xinlei Liu, Jian Zhang, Xiaojun Du, Tao Wang, Yin Teng, Chao Fan, Jianglun Li, Jieheng Wu, Zhu Zeng, Siyuan Yang.

   BACKGROUND: In lung adenocarcinoma (LUAD), the metabolism of amino acids (AAs) plays a crucial role in the growth, infiltration, and metastasis of tumor cells. Nevertheless, the potential of AA metabolism-associated genes (AAMRGs) to serve as prognostic indicators in LUAD remains ambiguous. Thus, this study sought to evaluate the prognostic value of AAMRGs in LUAD patients.
METHODS: Herein, we extracted LUAD transcriptomic information from two key repositories, namely The Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus. The non-negative matrix factorization (NMF) clustering technique was used to categorize the LUAD cases based on their AAM profiles before assessing the survival rates and composition of immune cells. Using limma software, shared dysregulated transcripts were identified across subgroups before functional annotation via DAVID, which comprised exploration of gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway. The prognostic framework was developed using five prognostic indicators through TCGA-derived LUAD specimens. We performed the analysis using singlevariable Cox, least absolute shrinkage and selection operator regression, and multi-factorial Cox regression. Molecular pathways between cohorts were compared with gene set enrichment analysis (GSEA). Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) analysis were utilized to validate the key genetic components of the model.
RESULTS: NMF clustering analysis was performed to categorize 497 LUAD patients into three distinct subgroups with obvious variations in the survival rates. The subtypes exhibited substantial disparities in immune cell populations, particularly in monocytes and mast cells. Analysis of 176 shared differentially expressed genes (DEGs) revealed enrichment in T lymphocyte stimulation, immunological reactions, and extra immune-related processes within the subgroups. The prognostic framework was constructed using biomarkers, such as ERO1LB, HPGDS, LOXL2, TMPRSS11E, and SLC34A2. Moreover, GSEA demonstrated a correlation between elevated risk and cell cycle processes, but lower risk was linked with arachidonic acid metabolic pathways. Analysis of 1128 DEGs revealed enrichment in various physiological processes, including cellular division, p53 signaling cascades, immunological responses, and additional pathways upon the comparison of high and low-risk cohorts. The RT-qPCR analysis confirmed elevated expression levels of ERO1LB and TMPRSS11E in LUAD specimens. Consistent with RT-qPCR analysis, the IHC results affirmed that the expression levels of ERO1LB and TMPRSS11E were increased in LUAD specimens.
CONCLUSION: The five identified AAMRGs in LUAD were validated and appropriately utilized to construct a risk assessment model that could potentially act as prognostic biomarkers for LUAD patients.

Keywords:  Lung adenocarcinoma (LUAD); amino acid metabolism-related genes; prognosis; risk model.

DOI:  https://doi.org/10.2174/0115665232364091250203090710
Cytokine. 2025 Apr 19. pii: S1043-4666(25)00090-0. [Epub ahead of print]191 156943

Downregulation of GFPT2 enhances cisplatin chemotherapy sensitivity in STK11/KRAS mutant non-small cell lung cancer by regulating the hexosamine biosynthesis pathway, resisting tumor growth.

Cheng Zhang, Xuelei Yin, Jun Jiang, Peng Wang, Yirong Wang.

   OBJECTIVE: To explore the role of GFPT2 in the sensitivity of STK11/KRAS lung cancer cells to cisplatin chemotherapy, and its underlying mechanism.
MATERIALS & METHODS: A549 and H460 cells were used to analyze the effect of GFPT2 on cisplatin chemotherapy sensitivity, as both carry KRAS mutations and H460 has LKB1 inactivation mutations, meeting the requirements of a KRAS/LKB1 co mutant tumor model. The levels of UDP-GlcNAc, OGT, OGA, and O-GlcNAc in the HBP pathway were also determined. To verify the potential role of HBP, we added OGT inhibitors. In vivo, we constructed a nude mouse model bearing A549 tumor to further validate the results of in vitro cell experiments.
RESULTS: GFPT2 silencing can significantly inhibit cell proliferation, invasion, and migration, promote cell apoptosis, and enhance the effect of cisplatin (p < 0.05). After OSMI-1 processing, GFPT2 enhances O-GlcNAc modification levels via the OGT-mediated HBP, thereby decreasing the sensitivity of STK11/KRAS mutant cells to cisplatin chemotherapy. In addition, GFPT2 silencing enhances the chemotherapy sensitivity of cisplatin and inhibits tumor growth, while overexpression of GFPT2 weakens this effect (p < 0.05). The above results provide new targets and combination therapy options for the clinical treatment of KRAS/LKB1 mutant lung cancer.
CONCLUSION: Our study found that inhibiting GFPT2 can enhance the chemotherapy sensitivity of cisplatin to STK11/KRAS/LKB1 mutant NSCLCs cells through the OGT mediated HBP pathway, filling a key gap in the chemotherapy resistance mechanism of KRAS/LKB1 mutant lung cancer.

Keywords:  Chemotherapy sensitivity; GFPT2; Hexosamine biosynthesis pathway; Lung cancer; STK11/KRAS co-mutation

DOI:  https://doi.org/10.1016/j.cyto.2025.156943