bims-meluca 2024-02-11 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–02–11
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

sPD-L1 and sPD-L2 in plasma of patients with lung cancer and their clinical significance.
Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.
PI3K/AKT/mTOR pathway, hypoxia, and glucose metabolism: Potential targets to overcome radioresistance in small cell lung cancer.
Plasma Lipidomics Profiling to Identify the Biomarkers of Diagnosis and Radiotherapy Response for Advanced Non-Small-Cell Lung Cancer Patients.
Metabolomics and lipidomics in non-small cell lung cancer.
Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk.
The efficacy and safety of immune-checkpoint inhibitors plus chemotherapy versus chemotherapy for non-small cell lung cancer: An updated systematic review and meta-analysis.
The Matrix Stiffness Coordinates the Cell Proliferation and PD-L1 Expression via YAP in Lung Adenocarcinoma.
Keratin gene signature expression drives epithelial-mesenchymal transition through enhanced TGF-β signaling pathway activation and correlates with adverse prognosis in lung adenocarcinoma.

Cytokine. 2024 Feb 06. pii: S1043-4666(24)00035-8. [Epub ahead of print]176 156532

sPD-L1 and sPD-L2 in plasma of patients with lung cancer and their clinical significance.

Shiyang Han, Yan Zhang, Jingzhi Yuan, Yi Wu, Yun Zhou, Yan Zhou, Xiaowei Li, Shuru Zhou.

   INTRODUCTION: Lung cancer is the leading cause of cancer death worldwide. We aim here to determine the soluble programmed death ligand-1 (sPD-L1) and soluble programmed death ligand-2 (sPD-L2) levels in the plasma of patients with lung cancer and evaluate the clinical significance.
METHODS: Plasma samples from 95 lung cancer patients and 55 healthy donors were collected, and the sPD-L1 and sPD-L2 levels were measured using the enzyme-linked immunosorbent assay. The correlations of the plasma sPD-L1 and sPD-L2 levels with clinicopathological status and survival of the patients were analyzed.
RESULTS: The sPD-L1 and sPD-L2 levels in plasma of lung cancer patients were 713.8 (240.6-3815) pg/ mL and 3233(1122-13955) pg/ mL, respectively, which were significantly higher than those of the health donors 618.6 (189.1-1149) pg/ mL and 2182 (1133-3471) pg/ mL, and the plasma levels of sPD-L1 are correlated with sPD-L2. ROC results showed that both sPD-L1 and sPD-L2 were potential biomarker for lung cancer, and with a higher accuracy level when combined with CEA. Patients with Higher plasma sPD-L1 level (>713.75 pg/ mL) are associated with poor overall survival in advanced lung cancer patients (197 days vs 643 days).
CONCLUSIONS: The combination of sPD-L1 and sPD-L2 could be used as adjunctive diagnostic, High level of plasma sPD-L1 rather than sPD-L2 is associated with poor prognosis in lung cancer patients.

Keywords:  Diagnosis biomarker; Lung cancer; Soluble programmed death ligand-1 (sPD-L1); Soluble programmed death ligand-2 (sPD-L2)

DOI:  https://doi.org/10.1016/j.cyto.2024.156532
Cancers (Basel). 2024 Jan 24. pii: 504. [Epub ahead of print]16(3):

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.

Marilyn Mathew, Nhi T Nguyen, Yangzom D Bhutia, Sathish Sivaprakasam, Vadivel Ganapathy.

  Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves the production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in the cancer-cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways that include amino acid metabolism, one-carbon metabolism, the pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of the expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates metabolic reprogramming, which has become a hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for the development of a new generation of therapeutics to treat cancer.

Keywords:  aerobic glycolysis; glutamine addiction; glutaminolysis; lactate receptors; nutrient transporters; oncogenes; oncometabolites; one-carbon metabolism; reductive carboxylation; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers16030504
Cancer Pathog Ther. 2023 Jan;1(1): 56-66

PI3K/AKT/mTOR pathway, hypoxia, and glucose metabolism: Potential targets to overcome radioresistance in small cell lung cancer.

Huan Deng, Yamei Chen, Peijing Li, Qingqing Hang, Peng Zhang, Ying Jin, Ming Chen.

  Small cell lung cancer (SCLC) is a highly aggressive tumor type for which limited therapeutic progress has been made. Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment, but most patients with SCLC acquire therapeutic resistance. Given the need for more effective therapies, better elucidation of the molecular pathogenesis of SCLC is imperative. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently activated in SCLC and strongly associated with resistance to ionizing radiation in many solid tumors. This pathway is an important regulator of cancer cell glucose metabolism, and its activation probably effects radioresistance by influencing bioenergetic processes in SCLC. Glucose metabolism has three main branches-aerobic glycolysis, oxidative phosphorylation, and the pentose phosphate pathway-involved in radioresistance. The interaction between the PI3K/AKT/mTOR pathway and glucose metabolism is largely mediated by hypoxia-inducible factor 1 (HIF-1) signaling. The PI3K/AKT/mTOR pathway also influences glucose metabolism through other mechanisms to participate in radioresistance, including inhibiting the ubiquitination of rate-limiting enzymes of the pentose phosphate pathway. This review summarizes our understanding of links among the PI3K/AKT/mTOR pathway, hypoxia, and glucose metabolism in SCLC radioresistance and highlights promising research directions to promote cancer cell death and improve the clinical outcome of patients with this devastating disease.

Keywords:  Glucose metabolism; PI3K/AKT/mTOR pathway; Radioresistance; Small cell lung cancer

DOI:  https://doi.org/10.1016/j.cpt.2022.09.001
J Lipids. 2024 ;2024 6730504

Plasma Lipidomics Profiling to Identify the Biomarkers of Diagnosis and Radiotherapy Response for Advanced Non-Small-Cell Lung Cancer Patients.

Minghe Lv, Shali Shao, Yajing Du, Xibing Zhuang, Xiangdong Wang, Tiankui Qiao.

Background: Advanced lung cancer that contributes to a heavy burden on medical institutions is the leading cause of cancer-related death and is often accompanied by metabolic disorders. In this study, we aimed to explore the biomarkers of diagnosis and radiotherapy response in non-small-cell lung cancer (NSCLC) patients by plasma lipidomics analysis.
Method: Using triple-quadrupole mass spectrometer analysis, our research characterized the plasma lipid metabolomics profile of 25 healthy controls and 31 advanced NSCLC patients in each of three different radiotherapy phases.
Results: The results showed altered lipid elements and concentrations among NSCLC patients with different radiotherapy phases, NSCLC subtypes, and different radiotherapeutic responses. We found that compared to the healthy controls, myelin-associated glycoprotein (MAG), phosphatidylinositol (PI), and phosphatidylserine (PS) were mainly and significantly altered lipid elements (> twofold, and p < 0.05) among NSCLC patients with different radiotherapy phases. Through comparison of lipid elements between bad and good responses of NSCLC patients with radiotherapy, the obviously declined phosphatidylglycerol (PG 18 : 0/14 : 0, 18 : 1/18 : 3, and 18 : 0/20 : 1) or markedly elevated PI (20 : 0/22 : 5 and 18 : 2/22 : 4) and phosphatidic acid (PA 14 : 0/20 : 4, 14 : 0/20 : 3, and 18 : 2/22 : 4) could indicate poor therapeutic response for NSCLC patients. The results of ROC curve analysis suggested that PG (18 : 0/20 : 1 and 18 : 0/14 : 0) could clearly predict the radiotherapeutic response for NSCLC patients, and PS (18 : 0/20 : 0) and cholesterol were the first two lipid components with the most potential for the diagnosis of advanced NSCLC.
Conclusion: Our results indicated that plasma lipidomics profiling might have a vital value to uncover the heterogeneity of lipid metabolism in healthy people and advanced NSCLC patients with different radiotherapy phase, and further to screen out radiotherapeutic response-specific biomarkers.

DOI: https://doi.org/10.1155/2024/6730504
Clin Chim Acta. 2024 Feb 05. pii: S0009-8981(24)00064-0. [Epub ahead of print]555 117823

Metabolomics and lipidomics in non-small cell lung cancer.

Wei Shi, Yizhen Cheng, Haihua Zhu, Longshan Zhao.

  Due to its insidious nature, lung cancer remains a leading cause of cancer-related deaths worldwide. Therefore, there is an urgent need to identify sensitive/specific biomarkers for early diagnosis and monitoring. The current study was designed to provide a current metabolic profile of non-small cell lung cancer (NSCLC) by systematically reviewing and summarizing various metabolomic/ lipidomic studies based on NSCLC blood samples, attempting to find biomarkers in human blood that can predict or diagnose NSCLC, and investigating the involvement of key metabolites in the pathogenesis of NSCLC. We searched all articles on lung cancer published in Elsevier, PubMed, Web of Science and the Cochrane Library between January 2012 and December 2022. After critical selection, a total of 31 studies (including 2768 NSCLC patients and 9873 healthy individuals) met the inclusion criteria, and 22 were classified as "high quality". Forty-six metabolites related to NSCLC were repeatedly identified, involving glucose metabolism, amino acid metabolism, lipid metabolism and nucleotide metabolism. Pyruvic acid, carnitine, phenylalanine, isoleucine, kynurenine and 3-hydroxybutyrate showed upward trends in all studies, citric acid, glycine, threonine, cystine, alanine, histidine, inosine, betaine and arachidic acid showed downward trends in all studies. This review summarizes the existing metabolomic/lipidomic studies related to the identification of blood biomarkers in NSCLC, examines the role of key metabolites in the pathogenesis of NSCLC, and provides an important reference for the clinical diagnosis and treatment of NSCLC. Due to the limited size and design heterogeneity of the existing studies, there is an urgent need for standardization of future studies, while validating existing findings with more studies.

Keywords:  Biomarkers; Blood; Lipidomics; Metabolomics; Non-small cell lung cancer; Systematic review

DOI:  https://doi.org/10.1016/j.cca.2024.117823
Cancer Causes Control. 2024 Feb 08.

Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk.

Jiajun Shi, Wanqing Wen, Jirong Long, Haoran Xue, Yaohua Yang, Ran Tao, Wei Pan, Xiao-Ou Shu, Qiuyin Cai.

   PURPOSE: We aimed to characterize genetic correlations and causal associations between circulating C-reactive protein (CRP) levels and the risk of lung cancer (LC).
METHODS: Leveraging summary statistics from genome-wide association studies of circulating CRP levels among 575,531 individuals of European ancestry, and LC risk among 29,266 cases and 56,450 controls, we investigated genetic associations of circulating CRP levels with the risk of overall lung cancer and its histological subtypes, by using linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analyses.
RESULTS: Significant positive genetic correlations between circulating CRP levels and the risk of LC and its histological subtypes were identified from LDSC regression, with correlation coefficients ranging from 0.12 to 0.26, and all false discovery adjusted p < 0.05. Univariable MR demonstrated a nominal association between CRP levels and an increased risk of lung squamous cell carcinoma (SCC) (inverse variance-weighted OR = 1.15, 95% CI 1.01-1.30). However, this association disappeared when multivariable MR included cigarettes per day and/or body mass index. By using our recently developed constrained maximum likelihood-based MR method, we identified significant associations of CRP levels with the risk of overall LC (OR 1.06, 95% CI 1.03-1.09), SCC (OR 1.06, 95% CI 1.02-1.09), and small cell lung cancer (SCLC, OR 1.09, 95% CI 1.03-1.15). Moreover, most univariable and multivariable MR analyses also revealed consistent CRP-SCLC associations.
CONCLUSION: There may be a genetic and causal association between circulating CRP levels and the risk of SCLC, which is in line with previous population-based observational studies.

Keywords:  C-reactive protein; Cigarette smoking; Genetic correlation; Lung cancer; Mendelian randomization

DOI:  https://doi.org/10.1007/s10552-024-01855-7
PLoS One. 2024 ;19(2): e0276318

The efficacy and safety of immune-checkpoint inhibitors plus chemotherapy versus chemotherapy for non-small cell lung cancer: An updated systematic review and meta-analysis.

Jing Kang, Jun Zhang, Zongsheng Tian, Ye Xu, Jiangbi Li, Mingxian Li.

BACKGROUND: Immune-checkpoint inhibitors(ICIs) combined with chemotherapy are emerging as an effective first-line treatment in advanced non-small cell lung cancer (NSCLC); however, reports on the magnitude of effectiveness and safety are conflicting.
METHODS: Relevant articles published before February 2022 were searched in PubMed, Embase, and the Cochrane Library. The study included all randomized controlled trials that evaluated ICIs with chemotherapy versus chemotherapy for the treatment of NSCLC. Among the outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs).
RESULTS: Our meta-analysis included a total of 12 studies. Overall analysis indicated that ICIs plus chemotherapy could significantly improve OS (HR = 0.79; 95% CI: 0.74-0.84; I2 = 44.4%, P = 0.055), PFS (HR = 0.62; 95% CI: 0.59-0.67; I2 = 75.3%, P = 0.000), and ORR (RR = 1.48; 95% CI: 1.27-1.73; I2 = 79.0%, P = 0.000) when compared to chemotherapy treatments. Subgroup analysis showed that PD-1/PD-L1 inhibitors combined with chemotherapy significantly improved OS, PFS, and ORR when compared with chemotherapy with decreased grade 1-2 TRAEs. In addition, female patients with nonsquamous histology might receive more OS benefit from ICIs plus chemotherapy when compared to chemotherapy alone. Despite the fact that CTLA-4 inhibitors combined with chemotherapy increased PFS, there were no benefits gained in OS nor ORR. When PD-L1/CTLA-4 inhibitors were added to chemotherapy, the risk of grade 3-5 adverse events increased whereas PD-1 inhibitors did not.
CONCLUSIONS: ICIs plus chemotherapy, compared with chemotherapy, were associated with significantly improved PFS, ORR, and OS in NSCLC therapy. However, PD-L1/CTLA-4 inhibitors plus chemotherapy could increase the risk of grade 3-5 adverse events, but not PD-1 inhibitors plus chemotherapy.

DOI: https://doi.org/10.1371/journal.pone.0276318
Cancers (Basel). 2024 Jan 31. pii: 598. [Epub ahead of print]16(3):

The Matrix Stiffness Coordinates the Cell Proliferation and PD-L1 Expression via YAP in Lung Adenocarcinoma.

Yeonhee Park, Dahye Lee, Jeong Eun Lee, Hee Sun Park, Sung Soo Jung, Dongil Park, Da Hyun Kang, Song-I Lee, Seong-Dae Woo, Chaeuk Chung.

  The extracellular matrix (ECM) exerts physiological activity, facilitates cell-to-cell communication, promotes cell proliferation and metastasis, and provides mechanical support for tumor cells. The development of solid tumors is often associated with increased stiffness. A stiff ECM promotes mechanotransduction, and the predominant transcription factors implicated in this phenomenon are YAP/TAZ, β-catenin, and NF-κB. In this study, we aimed to investigate whether YAP is a critical mediator linking matrix stiffness and PD-L1 in lung adenocarcinoma. We confirmed that YAP, PD-L1, and Ki-67, a marker of cell proliferation, increase as the matrix stiffness increases in vitro using the lung adenocarcinoma cell lines PC9 and HCC827 cells. The knockdown of YAP decreased the expression of PD-L1 and Ki-67, and conversely, the overexpression of YAP increased the expression of PD-L1 and K-67 in a stiff-matrix environment (20.0 kPa). Additionally, lung cancer cells were cultured in a 3D environment, which provides a more physiologically relevant setting, and compared to the results obtained from 2D culture. Similar to the findings in 2D culture, it was confirmed that YAP influenced the expression of PD-L1 and K-67 in the 3D culture experiment. Our results suggest that matrix stiffness controls PD-L1 expression via YAP activation, ultimately contributing to cell proliferation.

Keywords:  PD-L1; YAP; lung adenocarcinoma; matrix stiffness

DOI:  https://doi.org/10.3390/cancers16030598
Heliyon. 2024 Feb 15. 10(3): e24549

Keratin gene signature expression drives epithelial-mesenchymal transition through enhanced TGF-β signaling pathway activation and correlates with adverse prognosis in lung adenocarcinoma.

Gang Li, Jinbao Guo, Yunfei Mou, Qingsong Luo, Xuehai Wang, Wei Xue, Ting Hou, Tianyang Zeng, Yi Yang.

   Background: Lung adenocarcinoma (LUAD) stands as the foremost histological subtype of non-small-cell lung cancer, accounting for approximately 40% of all lung cancer diagnoses. However, there remains a critical unmet need to enhance the prediction of clinical outcomes and therapy responses in LUAD patients. Keratins (KRTs), serving as the structural components of the intermediate filament cytoskeleton in epithelial cells, play a crucial role in the advancement of tumor progression. This study investigated the prognostic significance of the KRT family gene and developed a KRT gene signature (KGS) for prognostic assessment and treatment guidance in LUAD.
Methods: Transcriptome profiles and associated clinical details of LUAD patients were meticulously gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The KGS score was developed based on the expression of five prognostic KRT genes (KRT7, KRT8, KRT17, KRT18, and KRT80), and the upper quartile of the KGS score was chosen as the cutoff. The Kaplan-Meier method was evaluated to compare survival outcomes between KGS-high and KGS-low groups. The underlying mechanism was further investigated by GSEA, GSVA, and other bioinformatic algorithms.
Results: High expression of the KGS signature exhibited a robust association with poorer overall survival (OS) in the TCGA-LUAD dataset (HR: 1.81; 95% CI: 1.35-2.42, P = 0.00011). The association was further corroborated in three external GEO cohorts, including GSE31210 (HR: 3.31; 95% CI: 1.7-6.47, P = 0.00017), GSE72094 (HR: 1.95; 95% CI: 1.34-2.85, P = 0.00057) and GSE26939 (HR: 3.19; 95% CI: 1.74-5.84, P < 0.0001). Interestingly, KGS-high tumors revealed enrichments in TGF-β and WNT-β catenin signaling pathways, exhibited heightened activation of the epithelial-mesenchymal transition (EMT) pathway and proved intensified tumor stemness compared to their KGS-low counterparts. Additionally, KGS-high tumor cells exhibited increased sensitivity to several targeted agents, including gefitinib, erlotinib, lapatinib, and trametinib, in comparison to KGS-low cells.
Conclusion: This study developed a KGS score that independently predicts the prognosis in LUAD. High expression of KGS score, accompanied by upregulation of TGF-β and WNT-β catenin signaling pathways, confers more aggressive EMT and tumor progression.

Keywords:  Drug sensitivity; EMT; Keratins; Lung adenocarcinoma (LUAD); Prognosis; TGF-β signaling; WNT-β catenin signaling

DOI:  https://doi.org/10.1016/j.heliyon.2024.e24549