bims-meluca 2022-09-25 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–09–25
eleven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes.
Formyl-Peptide Receptor 2 Signaling Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming of Lung Cancer Cells.
Multi-omics analysis to identify lung squamous carcinoma lactate metabolism-related subtypes and establish related index to predict prognosis and guide immunotherapy.
The Association Between Genetic Polymorphisms of Transporter Genes and Prognosis of Platinum-Based Chemotherapy in Lung Cancer Patients.
Pan-Cancer Analysis and Experimental Validation Identify ACOT7 as a Novel Oncogene and Potential Therapeutic Target in Lung Adenocarcinoma.
Obesity accelerates immune evasion of non-small cell lung carcinoma via TFEB-dependent upregulation of Siglec-15 and glycolytic reprogramming.
Functional expression of mitochondrial KCa3.1 channels in non-small cell lung cancer cells.
Causal associations between dietary antioxidant vitamin intake and lung cancer: A Mendelian randomization study.
Predictive value of baseline metabolic tumor volume for non-small-cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.
PAR2 promotes tumor-associated angiogenesis in lung adenocarcinoma through activating EGFR pathway.
Resveratrol Affects Sphingolipid Metabolism in A549 Lung Adenocarcinoma Cells.

Front Immunol. 2022 ;13 926304

A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes.

Leire Pedrosa, Carles Foguet, Helena Oliveres, Iván Archilla, Marta García de Herreros, Adela Rodríguez, Antonio Postigo, Daniel Benítez-Ribas, Jordi Camps, Miriam Cuatrecasas, Antoni Castells, Aleix Prat, Timothy M Thomson, Joan Maurel, Marta Cascante.

  Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/β-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches.

Keywords:  biomarker; immune checkpoint-based therapy; immunotherapy; metabolism; precision medicine

DOI:  https://doi.org/10.3389/fimmu.2022.926304
Antioxidants (Basel). 2022 Aug 29. pii: 1692. [Epub ahead of print]11(9):

Formyl-Peptide Receptor 2 Signaling Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming of Lung Cancer Cells.

Tiziana Pecchillo Cimmino, Ester Pagano, Mariano Stornaiuolo, Gabriella Esposito, Rosario Ammendola, Fabio Cattaneo.

  Glucose and glutamine play a crucial role in the metabolic reprogramming of cancer cells. Proliferating cells metabolize glucose in the aerobic glycolysis for energy supply, and glucose and glutamine represent the primary sources of carbon atoms for the biosynthesis of nucleotides, amino acids, and lipids. Glutamine is also an important nitrogen donor for the production of nucleotides, amino acids, and nicotinamide. Several membrane receptors strictly control metabolic reprogramming in cancer cells and are considered new potential therapeutic targets. Formyl-peptide receptor 2 (FPR2) belongs to a small family of GPCRs and is implicated in many physiopathological processes. Its stimulation induces, among other things, NADPH oxidase-dependent ROS generation that, in turn, contributes to intracellular signaling. Previously, by phosphoproteomic analysis, we observed that numerous proteins involved in energetic metabolism are uniquely phosphorylated upon FPR2 stimulation. Herein, we investigated the role of FPR2 in cell metabolism, and we observed that the concentrations of several metabolites associated with the pentose phosphate pathway (PPP), tricarboxylic acid cycle, nucleotide synthesis, and glutamine metabolism, were significantly enhanced in FPR2-stimulated cells. In particular, we found that the binding of specific FPR2 agonists: (i) promotes NADPH production; (ii) activates the non-oxidative phase of PPP; (iii) induces the expression of the ASCT2 glutamine transporter; (iv) regulates oxidative phosphorylation; and (v) induces the de novo synthesis of pyrimidine nucleotides, which requires FPR2-dependent ROS generation.

Keywords:  NADPH oxidase; formyl-peptide receptors; glucose metabolism; glutamine transporter; metabolic reprogramming; synthesis of pyrimidine nucleotides

DOI:  https://doi.org/10.3390/antiox11091692
Comput Struct Biotechnol J. 2022 ;20 4756-4770

Multi-omics analysis to identify lung squamous carcinoma lactate metabolism-related subtypes and establish related index to predict prognosis and guide immunotherapy.

Chenghao Wang, Tong Lu, Ran Xu, Shan Luo, Jiaying Zhao, Linyou Zhang.

  Lung squamous carcinoma (LUSC) is a malignant tumor of the respiratory system with highly heterogeneous characteristics. Lactate is the main product of aerobic glycolysis during the metabolic reprogramming of tumors. There is growing evidence that lactate metabolic processes have a broad and sophisticated impact on tumor phenotypic plasticity and tumor microenvironment (TME). However, the pattern of lactate metabolism in patients with LUSC and its impact on TME, phenotype, prognosis, and treatment have not been fully elucidated. In this study, we identified two subtypes with different lactate metabolism patterns in LUSC by non-negative matrix factorization and explored their multi-omics features. We observed that lactate metabolism levels in LUSC extensively influenced tumor immune infiltration patterns, adaptation to the hypoxia environment, and energy metabolic reprogramming. Subsequently, we constructed the lactate metabolism-related prognostic index (LMRPI) using Cox stepwise regression analysis. LMRPI showed excellent stability and accuracy, and based on the median value of LMRPI, LUAD were divided into two subgroups. The two subgroups have different patterns of immune infiltration and somatic mutations. Meanwhile, the two subgroups had different responsiveness to immune checkpoint inhibitor (ICI) therapies and different sensitivity to various chemotherapeutic and molecular targeting agents. In conclusion, we defined two subtypes with different lactate metabolism patterns in LUSC and extensively characterized their multi-omics profile. Furthermore, we developed LMRPI that predicts the prognosis of LUSC patients while also predicting their response to various adjuvant therapies, including immunotherapy, to guide their individualized treatment.

Keywords:  Immune checkpoint therapy; Immunogenomics; Lactate metabolism; Lung squamous carcinoma; Metabolic reprogramming; Prognosis biomarker

DOI:  https://doi.org/10.1016/j.csbj.2022.08.067
Pharmgenomics Pers Med. 2022 ;15 817-825

The Association Between Genetic Polymorphisms of Transporter Genes and Prognosis of Platinum-Based Chemotherapy in Lung Cancer Patients.

Jia He, Zhan Wang, Ting Zou, Ying Wang, Xiang-Ping Li, Juan Chen.

   Objective: Platinum-based chemotherapy is the first-line treatment of lung cancer. However, different individual and genetic variation effect therapy for lung cancer. The purpose of this study was to evaluate the association between transport genes genetic polymorphisms and the prognosis of platinum-based chemotherapy in lung cancer patients.
Methods: A series of 593 patients with treatment of platinum-based chemotherapy were recruited for this study. A total of 21 single-nucleotide polymorphisms in nine transporter genes were selected to investigate their associations with platinum-based chemotherapy prognosis.
Results: Patients with ABCG2 rs1448784 CC genotype had a significantly shorter PFS than CT or TT genotypes (Additive model: HR = 1.54, 95% CI = 1.02-2.35, P = 0.040). In stratification analysis, SLC22A2 rs316003, SLC2A1 rs4658 were related to PFS and AQP9 rs1867380, SLC2A1 rs3820589, SLC22A2 rs316003 indicated were related to OS of platinum-based chemotherapy prognosis.
Conclusion: Genetic polymorphisms of rs1448784 in ABCG2 might be potential clinical marker for predicting the prognosis of lung cancer patients treated with platinum-based chemotherapy.

Keywords:  SNPs; lung cancer; platinum-based chemotherapy; prognosis; single nucleotide polymorphisms; transporter gene

DOI:  https://doi.org/10.2147/PGPM.S375284
Cancers (Basel). 2022 Sep 18. pii: 4522. [Epub ahead of print]14(18):

Pan-Cancer Analysis and Experimental Validation Identify ACOT7 as a Novel Oncogene and Potential Therapeutic Target in Lung Adenocarcinoma.

Chao Zheng, Guochao Zhang, Kai Xie, Yifei Diao, Chao Luo, Yanqing Wang, Yi Shen, Qi Xue.

   BACKGROUND: Acyl-CoA thioesterase 7 (ACOT7) is of great significance in regulating cell cycle, cell proliferation, and glucose metabolism. The function of ACOT7 in pan-cancer and its capacity as a prognostic indicator in lung adenocarcinoma (LUAD) remains unknown. We intended to perform a comprehensive pan-cancer analysis of ACOT7 and to validate its value in LUAD.
METHODS: The expression levels, prognostic significance, molecular function, signaling pathways, and immune infiltration pattern of ACOT7 in 33 cancers were explored via systematic bioinformatics analysis. Multivariate Cox regression was applied to construct nomograms to predict patients' prognoses. Moreover, we conducted in vitro experiments including CCK8, scratch, Transwell, and Matrigel assays to further explore the function of ACOT7 in LUAD.
RESULTS: Patients with high ACOT7 expression have notably poorer long-term survival in many cancer types, including LUAD. Further enrichment analyses reveal that ACOT7 is involved in immune cells' infiltration and is substantially related to the cancer-immune microenvironment. ACOT7 could influence drug sensitivities, including afatinib, gefitinib, ibrutinib, lapatinib, osimertinib, sapitinib, taselisib, and PLX-4720 (all p < 0.01). A nomogram demonstrated a fair predictive value of ACOT7 in LUAD (C-index: 0.613, 95% CI: 0.568-0.658). The proliferation and migration of PC9 cells were significantly repressed when ACOT7 expression was downregulated.
CONCLUSION: As an oncogene, ACOT7 is critical in the tumor microenvironment of pan-cancer and might be a novel therapeutic target for LUAD.

Keywords:  ACOT7; LUAD; immune microenvironment; pan-cancer; prognosis

DOI:  https://doi.org/10.3390/cancers14184522
Cancer Lett. 2022 Sep 20. pii: S0304-3835(22)00405-0. [Epub ahead of print] 215918

Obesity accelerates immune evasion of non-small cell lung carcinoma via TFEB-dependent upregulation of Siglec-15 and glycolytic reprogramming.

Cai Zhang, Lijie Zhou, Songyang Li, Junwei Zhao, Xianchun Meng, Liwei Ma, Yongfeng Wang, Cai Li, Lu Zheng, Liang Ming.

  Although obesity contributes to tumor incidence and progression in various cancers, whether obesity impacts the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC) remains largely under-explored. We generated NSCLC xenograft model in diet-induced obese mice and identified that TFEB is critical to accelerate obesity-related NSCLC progression with mimic intrinsic functions on tumor biology. Mechanically, TFEB binds directly to Siglec-15 promoter to upregulate Siglec-15 expression and binds to Hk2 and Ldha promoters to enhance glycolytic flux in NSCLC cells, which restrain the expansion and cytotoxic function of CD8+ T cells while maintain suppressive Treg cells in TME, jointly promoting immune evasion of NSCLC cells in obesity. Blocking tumor TFEB improves the therapeutic efficiency of anti-PD-1 in obese mice. Altogether, our data identify essential roles of TFEB in remodeling immunosuppressive TME and promoting NSCLC development in obesity, providing scientific rational for TFEB as a potential biomarker to predict immune checkpoint blockade efficiency in obese NSCLC patients.

Keywords:  Immune checkpoint blockade; Immune evasion; Non-small cell lung carcinoma; Obesity; TFEB

DOI:  https://doi.org/10.1016/j.canlet.2022.215918
Pflugers Arch. 2022 Sep 24.

Functional expression of mitochondrial KCa3.1 channels in non-small cell lung cancer cells.

Etmar Bulk, Luca Matteo Todesca, Magdalena Bachmann, Ildiko Szabo, Marius Rieke, Albrecht Schwab.

  Lung cancer is one of the leading causes of cancer-related deaths worldwide. The Ca2+-activated K+ channel KCa3.1 contributes to the progression of non-small cell lung cancer (NSCLC). Recently, KCa3.1 channels were found in the inner membrane of mitochondria in different cancer cells. Mitochondria are the main sources for the generation of reactive oxygen species (ROS) that affect the progression of cancer cells. Here, we combined Western blotting, immunofluorescence, and fluorescent live-cell imaging to investigate the expression and function of KCa3.1 channels in the mitochondria of NSCLC cells. Western blotting revealed KCa3.1 expression in mitochondrial lysates from different NSCLC cells. Using immunofluorescence, we demonstrate a co-localization of KCa3.1 channels with mitochondria of NSCLC cells. Measurements of the mitochondrial membrane potential with TMRM reveal a hyperpolarization following the inhibition of KCa3.1 channels with the cell-permeable blocker senicapoc. This is not the case when cells are treated with the cell-impermeable peptidic toxin maurotoxin. The hyperpolarization of the mitochondrial membrane potential is accompanied by an increased generation of ROS in NSCLC cells. Collectively, our results provide firm evidence for the functional expression of KCa3.1 channels in the inner membrane of mitochondria of NSCLC cells.

Keywords:  KCa3.1; Mitochondria; NSCLC; ROS

DOI:  https://doi.org/10.1007/s00424-022-02748-x
Front Nutr. 2022 ;9 965911

Causal associations between dietary antioxidant vitamin intake and lung cancer: A Mendelian randomization study.

Hang Zhao, Xiaolin Jin.

   Background: Oxidative stress is currently considered to be closely related to the occurrence of respiratory tumors, especially lung cancer. Many observational studies have shown that increased antioxidant intake can reduce the risk of lung cancer, but the results are still controversial. Therefore, we performed a two-sample Mendelian randomized (MR) analysis to clarify the causal relationship between antioxidant vitamins and lung cancer.
Methods: To assess the causal effect of dietary antioxidant vitamin intake on lung cancer, we conducted a two-sample MR analysis and we extracted single-nucleotide polymorphisms (SNPs) that are associated with antioxidants from genome-wide association studies (GWASs) of the UK biobank. We gathered summary data for lung cancer from the International Lung Cancer Consortium (ILCCO), including 11,348 cases and 15,861 controls, and applied the inverse-variance weighted (IVW) method as the primary MR analysis, and performed a sensitivity analysis to verify the results.
Results: The results showed that higher dietary retinol intake was causally associated with lung cancer overall [odds ratio (OR) = 1.844, 95% CI, 1.359-2.502, p = 0.00009], squamous cell lung cancer (OR = 2.162, 95% CI, 1.117-4.183, p = 0.022), and lung adenocarcinoma (OR = 1.706, 95% CI, 1.084-2.685, p = 0.021). Additionally, carotene was positively correlated with lung adenocarcinoma (OR = 1.510, 95% CI, 1.002-2.276, p = 0.049). However, there was a non-significant relationship between the intake of other dietary antioxidants (vitamin C and vitamin E) and lung cancer.
Conclusion: Our research showed that dietary retinol intake has an adverse impact on lung cancer, and carotene might increase the risk of adenocarcinoma. This highlights the importance of revealing the underlying mechanisms of dietary antioxidant vitamins in lung cancer and delivers an important health message that dietary antioxidant vitamin intake may not be necessary for the prevention of lung cancer. It also provides a basis for future research.

Keywords:  Mendelian randomization; antioxidants; causation; lung cancer; vitamin intake

DOI:  https://doi.org/10.3389/fnut.2022.965911
Front Oncol. 2022 ;12 951557

Predictive value of baseline metabolic tumor volume for non-small-cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

Ke Zhu, Danqian Su, Jianing Wang, Zhouen Cheng, Yiqiao Chin, Luyin Chen, Chingtin Chan, Rongcai Zhang, Tianyu Gao, Xiaosong Ben, Chunxia Jing.

   Background: Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for advanced non-small-cell lung cancer (NSCLC) patients, highlighting the need for biomarkers to identify responders and predict the outcome of ICIs. The purpose of this study was to evaluate the predictive value of baseline standardized uptake value (SUV), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) derived from 18F-FDG-PET/CT in advanced NSCLC patients receiving ICIs.
Methods: PubMed and Web of Science databases were searched from January 1st, 2011 to July 18th, 2022, utilizing the search terms "non-small-cell lung cancer", "PET/CT", "standardized uptake value", "metabolic tumor volume", " total lesion glycolysis", and "immune checkpoint inhibitors". Studies that analyzed the association between PET/CT parameters and objective response, immune-related adverse events (irAEs) and prognosis of NSCLC patients treated with ICIs were included. We extracted the hazard ratio (HR) with a 95% confidence interval (CI) for progression-free survival (PFS) and overall survival (OS). We performed a meta-analysis of HR using Review Manager v.5.4.1.
Results: Sixteen studies were included for review and thirteen for meta-analysis covering 770 patients. As for objective response and irAEs after ICIs, more studies with consistent assessment methods are needed to determine their relationship with MTV. In the meta-analysis, low SUVmax corresponded to poor PFS with a pooled HR of 0.74 (95% CI, 0.57-0.96, P=0.02). And a high level of baseline MTV level was related to shorter PFS (HR=1.45, 95% CI, 1.11-1.89, P<0.01) and OS (HR, 2.72; 95% CI, 1.97-3.73, P<0.01) especially when the cut-off value was set between 50-100 cm3. SUVmean and TLG were not associated with the prognosis of NSCLC patients receiving ICIs.
Conclusions: High level of baseline MTV corresponded to shorter PFS and OS, especially when the cut-off value was set between 50-100 cm3. MTV is a potential predictive value for the outcome of ICIs in NSCLC patients.

Keywords:  PET/CT (18)F-FDG; immune checkpoint inhibitor; metabolic tumor volume; non-small-cell lung cancer; standardized uptake value

DOI:  https://doi.org/10.3389/fonc.2022.951557
Tissue Cell. 2022 Sep 06. pii: S0040-8166(22)00190-2. [Epub ahead of print]79 101918

PAR2 promotes tumor-associated angiogenesis in lung adenocarcinoma through activating EGFR pathway.

Yong Li, Huiqin Huang, Xiaoyun Chen, Nanding Yu, Xiangli Ye, Limin Chen, Zhenghui Huang.

   BACKGROUND: Metastasis of advanced lung adenocarcinoma (LUAD) is a key cause of cancer-related death, and angiogenesis is the main feature of tumor growth and metastasis.
METHODS: The expression level of F2R like trypsin receptor 1(F2RL1) which encodes protease-activated receptor 2 (PAR2) protein in LUAD tissues was analyzed by bioinformatics. The effects of F2RL1 overexpression/silencing on cell proliferation and sphere-forming were analyzed by Cell Counting Kit-8 and colony formation assays, stem cell sphere-forming assay, and angiogenesis assay, respectively. The F2RL1 mRNA expression level and the PAR2 protein expression level, vascular endothelial growth factor A (VEGFA), and epidermal growth factor receptor (EGFR) in lung cancer cell lines were evaluated by real-time quantitative polymerase chain reaction and western blot. The level of VEGFA secreted by lung cancer cells was analyzed by Enzyme-linked immunosorbent assay (ELISA). The effect of F2RL1-mediated EGFR signaling on angiogenesis was further explored by EGFR inhibitor AG1478.
RESULTS: F2RL1 was substantially up-regulated in LUAD tissues and cells, and overexpression of F2RL1 could promote proliferation and stem cell sphere-forming of lung cancer cell lines, as well as formation of blood vessels and branch points of human umbilical vein endothelial cells (HUVECs). Meanwhile, overexpression of F2RL1 significantly upregulated VEGFA expression and promoted EGFR phosphorylation. EGFR inhibitor AG1478 treatment significantly down-regulated pEGFR, and AG1478 treatment reversed the promoting effect of cancer cell cultured medium (oe-F2RL1) on HUVEC angiogenesis.
SIGNIFICANCE: In summary, this study revealed the molecular mechanism of PAR2 promoting LUAD angiogenesis by activating EGFR signaling pathway, which further improves our understanding of LUAD angiogenesis, and provides a potential therapeutic strategy for LUAD treatment.

Keywords:  Angiogenesis; EGFR; F2RL1; Lung adenocarcinoma; PAR2

DOI:  https://doi.org/10.1016/j.tice.2022.101918
Int J Mol Sci. 2022 Sep 17. pii: 10870. [Epub ahead of print]23(18):

Resveratrol Affects Sphingolipid Metabolism in A549 Lung Adenocarcinoma Cells.

Albena Momchilova, Roumen Pankov, Galya Staneva, Stefan Pankov, Plamen Krastev, Evgenia Vassileva, Rusina Hazarosova, Nikolai Krastev, Bozhil Robev, Biliana Nikolova, Adriana Pinkas.

  Resveratrol is a naturally occurring polyphenol which has various beneficial effects, such as anti-inflammatory, anti-tumor, anti-aging, antioxidant, and neuroprotective effects, among others. The anti-cancer activity of resveratrol has been related to alterations in sphingolipid metabolism. We analyzed the effect of resveratrol on the enzymes responsible for accumulation of the two sphingolipids with highest functional activity-apoptosis promoting ceramide (CER) and proliferation-stimulating sphingosine-1-phosphate (S1P)-in human lung adenocarcinoma A549 cells. Resveratrol treatment induced an increase in CER and sphingosine (SPH) and a decrease in sphingomyelin (SM) and S1P. Our results showed that the most common mode of CER accumulation, through sphingomyelinase-induced hydrolysis of SM, was not responsible for a CER increase despite the reduction in SM in A549 plasma membranes. However, both the activity and the expression of CER synthase 6 were upregulated in resveratrol-treated cells, implying that CER was accumulated as a result of stimulated de novo synthesis. Furthermore, the enzyme responsible for CER hydrolysis, alkaline ceramidase, was not altered, suggesting that it was not related to changes in the CER level. The enzyme maintaining the balance between apoptosis and proliferation, sphingosine kinase 1 (SK1), was downregulated, and its expression was reduced, resulting in a decrease in S1P levels in resveratrol-treated lung adenocarcinoma cells. In addition, incubation of resveratrol-treated A549 cells with the SK1 inhibitors DMS and fingolimod additionally downregulated SK1 without affecting its expression. The present studies provide information concerning the biochemical processes underlying the influence of resveratrol on sphingolipid metabolism in A549 lung cancer cells and reveal possibilities for combined use of polyphenols with specific anti-proliferative agents that could serve as the basis for the development of complex therapeutic strategies.

Keywords:  ceramide; lung cancer cells; resveratrol; sphingolipid metabolism; sphingosine-1-phosphate

DOI:  https://doi.org/10.3390/ijms231810870