bims-meluca 2025-09-28 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–09–28
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

A cohort study of circulating biomarkers to predict the efficacy and prognosis of immune combination therapy in non-small cell lung cancer.
Metformin sensitizes non-small cell lung cancer to CDK4/6 inhibitor treatment by reducing lysosomal trapping.
The role of glutamine metabolism and ASCT2/SLC1A5 transporter on insulin resistance and endoplasmic reticulum stress in 3T3-L1 adipocytes.
Senescence-associated gene signatures predict survival in lung cancer: a multi-cohort analysis.
Lactoferrin treatment activates acetylcholinesterase, decreasing acetylcholine levels in non-small cell lung cancer (NSCLC) cell culture supernatants, inhibiting cell survival.
Dietary α-Ketoglutarate delays lung adenocarcinoma in females and modulates TBX5-associated transcriptional programs and the immune microenvironment.

Oncologist. 2025 Sep 25. pii: oyaf306. [Epub ahead of print]

A cohort study of circulating biomarkers to predict the efficacy and prognosis of immune combination therapy in non-small cell lung cancer.

Yanxia Liu, Xiaomi Li, Minghang Zhang, Yuan Gao, Ying Wang, Mingming Hu, Shaofa Xu, Tongmei Zhang.

   BACKGROUND: Immune checkpoint inhibitors (ICIs) bring significant clinical benefits to non-small cell lung cancer (NSCLC), and convenient peripheral blood markers are still lacking. Human circulating cytokines play an important role in tumor growth and metastasis, and exploring their value in NSCLC immunotherapy helps to achieve precise treatment of patients.
METHODS: This study was a mixed design of prospective blood collection and retrospective data collection. Patients with NSCLC who received the first ICI combined with chemotherapy were included, and plasma samples were collected at baseline and after two cycles of treatment. MILLIPLEX ® MAP technology was used to detect the levels of a panel of cancer biomarkers and to explore the predictive potential of cytokines for survival and treatment response in such patients.
RESULTS: Baseline blood samples were collected from 79 NSCLC patients in this study, and survival analysis showed that high expression of four cytokines, carbohydrate antigen 125 (CA125), cytokeratin 19 fragment (CYFRA 21-1), human epididymis protein 4 (HE4), and hepatocyte growth factor (HGF), was associated with shorter overall survival (OS) and progression-free survival (PFS), low levels of stem cell factor (SCF) tended to have better OS than patients with high levels of SCF, and multivariate Cox regression showed that high levels of HGF were independent risk factors for OS (HR = 1.92, 95% CI: 1.02-3.70, P = 0.042) and PFS (HR = 3.23, 95% CI: 1.75-5.88, P < 0.001). HGF was more predictive of one-year survival and six-month progression-free survival than PD-L1 expression. In addition, we collected blood samples from 53 patients after two cycles of treatment, CYFRA 21-1, HGF, interleukin-8 (IL-8), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were associated with patient survival, and patients with increased HGF after treatment had shorter survival. In patients whose tumors responded to treatment, CA125 and CYFRA 21-1 levels increased from baseline, whereas soluble apoptosis-related factor (sFas) levels decreased.
CONCLUSIONS: Soluble cytokines, especially HGF, have certain clinical value in immunotherapy combination therapy and prognosis of NSCLC patients and are worthy of validation in a larger prospective cohort and exploration of their potential mechanisms.

Keywords:  Circulating cytokines; Hepatocyte growth factor; Immune checkpoint inhibitors; Non-small cell lung cancer; Prognostic markers

DOI:  https://doi.org/10.1093/oncolo/oyaf306
Sci China Life Sci. 2025 Sep 23.

Metformin sensitizes non-small cell lung cancer to CDK4/6 inhibitor treatment by reducing lysosomal trapping.

Yaqi Liu, Yalei Wang, Ni Zhang, Haijuan Xiong, Lipan Zhao, Ying Qi, Jiping Xie, Xiaofeng Duan, Dongsheng Yue, Shuo Qie.

  The hyperactivation of cyclin D1-CDK4/6 signaling is correlated with tumour metastasis and poor prognosis in patients with non-small cell lung cancer (NSCLC), suggesting the therapeutic potential of targeting CDK4/6 to treat NSCLC. Our preliminary data indicate CDK4/6 inhibitors are sequestered in lysosomes in NSCLC cells, a phenomenon that is termed lysosomal trapping and is associated with intrinsic drug resistance. It is promising to search for new compounds that could be co-administered with CDK4/6 inhibitors to reduce lysosomal trapping, thereby enhancing the sensitivity of NSCLC cells. Here, we find that metformin reduces the activity of the lysosomal pathway through genome-wide analyses; consistently, metformin reduces lysosomal trapping of CDK4/6 inhibitors in NSCLC cells. Biologically, metformin enhances the suppressive effects of CDK4/6 inhibitors on cell cycle progression, cell proliferation, and colony formation. Mechanistically, metformin suppresses lysosomal trapping by: (i) reducing translocation of TFEB into nuclei that leads to decreased lysosome biogenesis and (ii) disrupting lysosomal acidic environment through reduced V-ATPase activity and decreased interaction between LAMP1/LAMP2 and TMEM175. Clinically, combined treatment with metformin and CDK4/6 inhibitors decreased the growth of mouse xenografts and tumour cell organoids. In conclusion, our study provides a new mechanism for utilizing metformin to treat NSCLC by reducing lysosomal trapping, thereby increasing cellular sensitivity to CDK4/6 inhibitors.

Keywords:  CDK4/6 inhibitors; lysosomal trapping; metformin; non-small cell lung cancer; therapeutic efficacy

DOI:  https://doi.org/10.1007/s11427-024-3015-1
Cytotechnology. 2025 Oct;77(5): 177

The role of glutamine metabolism and ASCT2/SLC1A5 transporter on insulin resistance and endoplasmic reticulum stress in 3T3-L1 adipocytes.

Gulizar Aydogdu, Benan Pelin Sermikli, Sumer Aras, Erkan Yilmaz.

  Obesity is one of the major health issues of recent times. It is known that obesity increases endoplasmic reticulum (ER) stress, contributing to the development of insulin resistance in type-2 diabetes. This study investigates the relationship of glutamine metabolism with insulin resistance and ER stress under obese conditions. Using differentiated 3T3-L1 adipocytes, we demonstrate that increased glutamine supplementation enhances insulin sensitivity and reduces ER stress. Enhanced glutamine treatment also upregulated key amino acid transporters, Alanine-Serine-Cysteine Transporter 2 (ASCT2), L-type Amino Acid Transporter 1 (LAT1), and Cystine/Glutamate Antiporter (xCT), activating the mammalian target of rapamycin (mTOR) pathway. To investigate the specific role of ASCT2, its expression was reduced in 3T3-L1 fibroblasts via sh-ASCT2 transfection prior to adipogenic differentiation. Interestingly, the levels of other selected glutamine-glutamate transporters, LAT1 and xCT, were also decreased. Knockdown of ASCT2 via shRNA significantly impaired adipocyte differentiation. The significant reduction of intracellular lipid accumulation leads to decreased ER stress and insulin resistance in sh-ASCT2 adipocytes. Metabolomic analysis results revealed that intracellular glutamine and malate levels increased during fat cell differentiation. The glutamine levels decreased in sh-ASCT2 adipocytes, while malate levels remained unchanged. In conclusion, glutamine may enhance insulin sensitivity by modulating ER stress and influencing transporter expression. ASCT2 might play a role in adipocyte differentiation, and evidence indicates that ASCT2 inhibition could be associated with reduced adipogenesis and improved insulin signaling, suggesting its potential relevance as a therapeutic target in obesity-related insulin resistance. Further studies are needed to clarify the context-dependent mechanisms by which glutamine and ASCT2 regulate metabolic stress adaptation.

Keywords:  ASCT2; Endoplasmic reticulum stress; Glutamine transporter; Insulin resistance; Obesity

DOI:  https://doi.org/10.1007/s10616-025-00844-1
Geroscience. 2025 Sep 27.

Senescence-associated gene signatures predict survival in lung cancer: a multi-cohort analysis.

Zoltán Ungvári, Otília Menyhart, Alberto Ocana, Mónika Fekete, Andrea Lehoczki, Balázs Győrffy.

  Lung cancer is a leading cause of cancer-related mortality worldwide and is predominantly diagnosed in older adults, underscoring the need to explore aging-related biological mechanisms that influence disease progression and prognosis. Cellular senescence, a hallmark of aging, plays a dual role in cancer by contributing to both tumor suppression and tumor promotion through its influence on tumor growth, modulation of the tumor microenvironment, the senescence-associated secretory phenotype (SASP), and response to therapy. In this study, we evaluated the prognostic significance of senescence-related gene expression in lung cancer using three independent gene signatures, including the SenMayo gene set and two additional curated lists. Transcriptomic and clinical data from publicly available datasets were analyzed using Cox regression, Kaplan-Meier survival analysis, and multivariate modeling. All three senescence signatures were significantly associated with overall survival, with the SenMayo signature showing the most robust and consistent prognostic power. Notably, higher expression of senescence-associated genes was associated with improved survival in the overall lung cancer cohort and in lung adenocarcinoma, while a more heterogeneous pattern emerged in squamous cell carcinoma. Although hazard ratios varied among the gene sets, their broadly concordant associations with clinical outcomes highlight the biological relevance and context dependence of senescence in lung cancer. These findings suggest that senescence-associated gene expression may serve as a valuable prognostic biomarker and offer mechanistic insights into tumor behavior. Our results contribute to the growing body of gero-oncology research and emphasize the need for tumor-specific exploration of aging-related processes in cancer.

Keywords:  Aging; Biomarkers; Gene expression; Gero-oncology; Lung cancer; Prognosis; SASP; SenMayo; Senescence; Senolytics

DOI:  https://doi.org/10.1007/s11357-025-01894-1
FEBS Open Bio. 2025 Sep 23.

Lactoferrin treatment activates acetylcholinesterase, decreasing acetylcholine levels in non-small cell lung cancer (NSCLC) cell culture supernatants, inhibiting cell survival.

Stuti Goel, Caroline Wozniak, Aya Sabri, Ben Haddad, Brooke Lopo, Alvaro Cobos, Sarah Sarofim, Jeffrey Guthrie, Deborah Heyl, Hedeel Guy Evans.

  Lactoferrin (Lf) is a multifunctional glycoprotein of the transferrin family which has shown to efficiently block cell migration and/or invasion in a wide range of cancer cell models. The objective of this study was to further understand how Lf targets cancer cells by examining the effect of acetylcholine (ACh) levels on Lf signaling using A549 (p53 wild-type) and H1299 (p53-null) nonsmall cell lung cancer (NSCLC) cell lines. Treatment with Lf reduced cell viability more effectively in A549 cells than in H1299 cells. The half maximal inhibitory concentration (IC50) of Lf for A549 and H1299 was 8.97 ± 1.4 and 35.03 ± 4.2 mg·mL-1, respectively. To uncover the potential molecular mechanism involved in the decreased cell viability observed in A549 cell following Lf treatment, the activity of tumor suppressor (p53), acetylcholinesterase (AChE), and ACh levels were measured. Treatment of A549 cells with Lf led to ~ 1.50-fold activation of p53, ~ 1.60-fold activation of AChE, and ~ 1.80-fold decrease in ACh levels. Vascular endothelial growth factor (VEGF) levels also decreased in cell culture supernatants upon treatment with Lf in both cell lines, and in A549 cells, the decrease occurred in a manner dependent on p53 and AChE. Given previous reports on the role of Lf in apoptosis induction, we examined AKT activity following Lf treatment and showed that AKT activity decreased ~ 1.95-fold in A549 cells and ~ 1.50-fold in H1299 cells. Furthermore, Lf-induced activation of caspase-3 was diminished by A549 cell cotreatment with siRNA targeted against p53 and/or AChE and increased by inhibiting the function of VEGF and/or AKT in both cell lines. In conclusion, this study identifies a mechanism wherein ACh concentrations in the cell culture supernatant attenuate the impact of Lf on NSCLC cell viability. These findings provide preliminary insight into the complex actions of Lf and suggest that the Lf-AChE-ACh pathway may warrant further study as a potential target in NSCLC.

Keywords:  acetylcholine; cell viability; lactoferrin; lung cancer; p53; vascular endothelial growth factor

DOI:  https://doi.org/10.1002/2211-5463.70125
bioRxiv. 2025 Sep 21. pii: 2025.09.19.677388. [Epub ahead of print]

Dietary α-Ketoglutarate delays lung adenocarcinoma in females and modulates TBX5-associated transcriptional programs and the immune microenvironment.

Martin Alcaraz, Aparamita Pandey, Mia Santiago, Camelia Dumitras, Leilani Pradis, Estefany Gomez, Adriana Soto, Pasquale Saggese, Bin Liu, Steven M Dubinett, Claudio Scafoglio.

Lung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer-related mortality, underscoring the need for new chemopreventive strategies. α-Ketoglutarate (α-KG), a tricarboxylic acid cycle metabolite and dioxygenase cofactor, links cellular metabolism to chromatin regulation. Here, we show that dietary α-KG remodels LUAD in a sex-dependent manner. In female mice, α-KG reduced tumor area, decreased repressive histone marks (H3K27me3, H3K9me3), and upregulated TBX5 and myogenesis-associated genes. In male mice, α-KG-treated male mice exhibited increased tumor area, elevated H3K27me3, and immune remodeling characterized by CD8⁺ T cell expansion and transcriptomic signatures of T cell exhaustion. Analysis of human LUAD revealed that TBX5 expression is enriched in female tumors and associated with improved survival, suggesting it may serve as a marker of favorable outcome. Together, these findings support α-KG as an epigenetic modulator with potential chemopreventive activity in lung cancer and highlight the importance of incorporating sex as a biological variable in preclinical studies.

DOI: https://doi.org/10.1101/2025.09.19.677388