bims-meluca 2021-07-18 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–07–18
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

The role of metformin on lung cancer survival: the first systematic review and meta-analysis of observational studies and randomized clinical trials.
Extracellular vesicles derived from lung cancer cells exposed to intermittent hypoxia upregulate programmed death ligand 1 expression in macrophages.
Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment.
Identification of a predictive metabolic signature of response to immune checkpoint inhibitors in non-small cell lung cancer: METABO-ICI clinical study protocol.
Aberrant expression of HIF3A in plasma of patients with non-small cell lung cancer and its clinical significance.
The Relationship of Diabetes Mellitus to Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.
Role of NRF2 in immune modulator expression in developing lung.
Development and Validation of a Robust Ferroptosis-Related Prognostic Signature in Lung Adenocarcinoma.

J Cancer Res Clin Oncol. 2021 Jul 15.

The role of metformin on lung cancer survival: the first systematic review and meta-analysis of observational studies and randomized clinical trials.

Suzan Brancher, Ana Elisa Ribeiro, Tatiana Natasha Toporcov, Elisabete Weiderpass.

   PURPOSE: To assess the effects of metformin use on lung cancer (LC) survival according to summarized results from observational studies (OBs) and randomized clinical trials (RCTs).
METHODS: We systematically searched electronic databases and, to our knowledge, for the first time, RCTs were included in a systematic review and meta-analysis about the role of metformin on LC survival. We carried out meta-analyses separately for OBs and RCTs. Analyses for overall survival (OS) concerning OBs were stratified by studies with and without time-dependent approach. Subgroup analyses were adopted for OBs to identify the sources of heterogeneity. Included studies were assessed for quality.
RESULTS: We identified ten OBs and four RCTs. For OBs, metformin use was associated with improved OS for LC patients. Only two studies used time-dependent approach in which a higher ratio was found when compared to the non-use of the time-dependent analysis in eight studies. OBs were classified as high quality but the risk of bias was "unclear" in eight OBs due to absence of the time-dependent analysis. For RCTs, metformin use was not beneficial for OS and neither for progression-free survival. Heterogeneous quality was found among RCTs. Sources of bias that could alter significantly the results or raise doubts were identified in RCTs.
CONCLUSION: Time-dependent analysis should be considered an appropriate strategy for OBs focused on the metformin use for LC patients' survival, and further studies applying this approach are required. More well-designed RCTs are needed to provide consistent results for the association between metformin use and LC survival.

Keywords:  Lung cancer; Meta-analysis; Metformin; Randomized clinical trials; Survival; Systematic review

DOI:  https://doi.org/10.1007/s00432-021-03728-x
Sleep Breath. 2021 Jul 12.

Extracellular vesicles derived from lung cancer cells exposed to intermittent hypoxia upregulate programmed death ligand 1 expression in macrophages.

Yuanling Liu, Minzhen Lu, Jianan Chen, Siqi Li, Yiyu Deng, Shifang Yang, Qiong Ou, Jing Li, Ping Gao, Zeru Luo, Ping Yuan, Jianlong Tan, Xinglin Gao.

   PURPOSE: Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), compromises immune surveillance through the upregulation of programmed cell death-1 ligand (PD-L1). Tumor-released extracellular vesicles (EVs) have been reported to modulate immunosuppressive activities. We investigated whether or not EVs derived from intermittent hypoxic lung cancer cells can alter the expression of PD-L1 in macrophages.
METHODS: The expression of PD-L1+monocytes from 40 patients with newly diagnosed non-small-cell lung cancer (NSCLC) and with (n=21) or without (n=19) OSA were detected. Plasma EVs isolated from NSCLC patients with moderate-severe OSA (n=4) and without OSA (n=4) were co-cultured with macrophages. A549 cells were exposed to normoxia or IH (48 cycles of 5 min of 1% O2 hypoxia, followed by 5 min of normoxia). EVs were isolated from cell supernatant and were co-cultured with macrophages differentiated from THP-1. PD-L1 and hypoxia-inducible factor-1 α (HIF-1α) expressions were measured by flow cytometry, immunofluorescence, and Western blot analysis.
RESULTS: PD-L1+monocytes were elevated in NSCLC patients with OSA and increased with the severity of OSA and nocturnal desaturation. PD-L1+ macrophages were induced by EVs from NSCLC patients with OSA and positively correlated with HIF-1α expressions. EVs from IH-treated A549 can promote PD-L1 and HIF-1α expression in macrophages and the upregulation of PD-L1 expression was reversed by specific HIF-1α inhibitor.
CONCLUSION: IH can enhance the function of EVs derived from lung cancer cells to aggravate immunosuppressive status in macrophages. HIF-1α may play an important role in this process.

Keywords:  Extracellular vesicle; Macrophage; Non-small-cell lung cancer; Obstructive sleep apnea; Programmed cell death-1 ligand

DOI:  https://doi.org/10.1007/s11325-021-02369-1
Nat Rev Cancer. 2021 Jul 09.

Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment.

Samuel A Kerk, Thales Papagiannakopoulos, Yatrik M Shah, Costas A Lyssiotis.

Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.

DOI: https://doi.org/10.1038/s41568-021-00375-9
Respir Med Res. 2021 Jun 07. pii: S2590-0412(21)00034-9. [Epub ahead of print]80 100845

Identification of a predictive metabolic signature of response to immune checkpoint inhibitors in non-small cell lung cancer: METABO-ICI clinical study protocol.

Sarah Sannicolo, Matteo Giaj Levra, Audrey Le Gouellec, Caroline Aspord, Julien Boccard, Laurence Chaperot, Bertrand Toussaint, Denis Moro-Sibilot, Dalil Hannani, Anne-Claire Toffart.

   BACKGROUND: Immune checkpoints inhibitors (ICI) are becoming new standards of care for the treatment of non-small cell lung cancer (NSCLC), both as first (alone or in association with chemotherapy) and second line. However, no powerful predictive biomarker of therapeutic response to ICI has been found to date. It has been recently shown that microbiota composition could influence the ability of patients to respond to ICI. Indeed, the microbiota produces circulating metabolites that will subsequently act on immune system, the investigators hypothesized that plasma metabolic signature, reflecting a global microbiota function, could represent a predictive biomarker of response to ICI.
METHODS: Monocentric prospective study. Primary objective is to identify baseline metabolic signature (metabolomics analysis by mass spectrometry) associated to ICI response. Secondary objectives are to link metabolic signature with microbiota composition (metagenomics analysis RNA 16S) and immune profile, and altogether with clinic response to ICI. The study will include 60 NSCLC patients treated by ICI in 1st, 2nd or 3rd line of treatment at the Grenoble Alpes University hospital (CHUGA) in 18 months. Patients that have received antibiotic or steroid treatment, 2 or 4 weeks before ICI initiation, respectively, will be excluded. Blood and feces will be collected prior to, at 2 months after ICI treatment initiation, and at 6 months or at progression.
EXPECTED RESULTS: We expect to highlight a metabolic profile predictive of response to ICI. By identifying factors associated with early progression, we could avoid to treat potential non-responding patients. Moreover, by restoring a favorable microbiota, patients' ability to respond to these treatments might be restored.

Keywords:  Immunotherapy; Metabolism; Microbiota; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.resmer.2021.100845
J Clin Lab Anal. 2021 Jul 10. e23889

Aberrant expression of HIF3A in plasma of patients with non-small cell lung cancer and its clinical significance.

Liang Wei, Na Yuan, Yingying Chen, Pingping Gong.

   BACKGROUND: Hypoxia-inducible factors (HIFs) have been evaluated in various cancers and diseases. However, the specific role of hypoxia-inducible factor 3 alpha (HIF3A) in non-small cell lung cancer (NSCLC) remains controversial.
MATERIALS AND METHODS: We investigated HIF3A mRNA expression in the plasma and tumor tissues of patients with NSCLC and explored its clinical significance. Plasma samples from 103 cases of lung adenocarcinoma (LUAD) and 96 cases of lung squamous cell carcinoma (LUSC), and tumor-adjacent normal tissues from 58 LUAD and 62 LUSC cases were retrospectively evaluated at the No.8 People's Hospital of Qing Dao. HIF3A expression was explored using RT-qPCR. The clinical significance of HIF3A was evaluated in the plasma and tumor tissues using the receiver operating curve (ROC) and the area under the curve (AUC).
RESULTS: Hypoxia-inducible factor 3 alpha expression was notably downregulated in the plasma or tumor tissues of patients with LUAD and LUSC, compared with the healthy control group or adjacent normal tissues. Furthermore, HIF3A expression had a significant positive correlation in the plasma and tumor tissues of LUAD and LUSC patients. Meanwhile, the ROC-AUCs achieved a significantly higher range, from 0.84 to 0.93, with the plasma or tumor tissues of NSCLC patients. Thus, HIF3A expression was not only correlated with plasma and tumor tissues, but also showed potential significance in NSCLC.
CONCLUSION: Hypoxia-inducible factor 3 alpha is aberrantly detectable in NSCLC patients in the plasma and tumor tissues. HIF3A may be involved in hypoxic responses during the development and occurrence of NSCLC.

Keywords:  HIF3A; hypoxia; mRNA gene; non-small cell lung cancer; plasma

DOI:  https://doi.org/10.1002/jcla.23889
Oncology. 2021 Jul 09. 1-7

The Relationship of Diabetes Mellitus to Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

Oded Jacobi, Yosef Landman, Daniel Reinhorn, Oded Icht, Michal Sternschuss, Ofer Rotem, Inbar Finkel, Aaron M Allen, Elizabeth Dudnik, Daniel A Goldstein, Alona Zer.

   INTRODUCTION: Immune checkpoint inhibitors (ICI) are the new standard therapy in patients with metastatic NSCLC (mNSCLC). Metformin, previously associated with improved chemotherapy efficacy in diabetic and nondiabetic cancer patients, was recently associated with increased ICI efficacy. In this study, we aimed to explore the correlations between diabetes mellitus (DM), metformin use, and benefit from ICI in mNSCLC patients.
METHODS: All mNSCLC patients treated with ICI in our center between February 2015 and April 2018 were identified. Demographic and clinical data were extracted retrospectively. Cox proportional hazards regression, t tests, and χ2 tests were employed to evaluate associations of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), with DM status, metformin use, and HbA1c levels, as appropriate.
RESULTS: Of 249 mNSCLC patients treated with ICI, 57 (22.8%) had DM. Thirty-seven (64.9% of all diabetic patients) patients were treated with metformin. A significant negative correlation of DM with PFS and OS was demonstrated (HR 1.5 [1.01-2.06], p = 0.011, and HR 1.5 [1.08-2.08], p = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61-1.93], p = 0.79, and HR 1.29 [0.69-2.39], p = 0.42, respectively). There were no differences between groups with respect to ORR and DCR.
CONCLUSION: Our data show a potential negative relationship between DM and ICI efficacy in mNSCLC patients. In contrast to reports with chemotherapy, we found no positive relationship between metformin use and ICI therapy in diabetic patients with mNSCLC. Further studies are needed to evaluate the effect of metformin in nondiabetic mNSCLC patients.

Keywords:  Diabetes; Immune checkpoint inhibitors; Immunotherapy; Metformin; Non-small cell lung cancer

DOI:  https://doi.org/10.1159/000516671
FASEB J. 2021 Aug;35(8): e21758

Role of NRF2 in immune modulator expression in developing lung.

Ritu Mishra, Afshan Fathima Nawas, Carole R Mendelson.

  After birth, the alveolar epithelium is exposed to environmental pathogens and high O2 tensions. The alveolar type II cells may protect this epithelium through surfactant production. Surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with surfactant phospholipid synthesis. Herein, we observed that the redox-regulated transcription factor, NRF2, and co-regulated C/EBPβ and PPARγ, were markedly induced during cAMP-mediated differentiation of cultured human fetal lung (HFL) epithelial cells. This occurred with enhanced expression of immune modulators, SP-A, TDO2, AhR, and NQO1. Like SP-A, cAMP induction of NRF2 was prevented when cells were exposed to hypoxia. NRF2 knockdown inhibited induction of C/EBPβ, PPARγ, and immune modulators. Binding of endogenous NRF2 to promoters of SP-A and other immune modulator genes increased during HFL cell differentiation. In mouse fetal lung (MFL), a developmental increase in Nrf2, SP-A, Tdo2, Ahr, and Nqo1 and decrease in Keap1 occurred from 14.5 to 18.5 dpc. Developmental induction of Nrf2 in MFL was associated with increased nuclear localization of NF-κB p65, a decline in p38 MAPK phosphorylation, increase in the MAPK phosphatase, DUSP1, induction of the histone acetylase, CBP, and decline in the histone deacetylase, HDAC4. Thus, together with surfactant production, type II cells protect the alveolar epithelium through increased expression of NRF2 and immune modulators to prevent inflammation and oxidative stress. Our findings further suggest that lung cancer cells have usurped this developmental pathway to promote immune tolerance and enhance survival.

Keywords:  NRF2; SP-A; development; fetal lung; immune modulators; oxygen tension

DOI:  https://doi.org/10.1096/fj.202100129RR
Front Cell Dev Biol. 2021 ;9 616271

Development and Validation of a Robust Ferroptosis-Related Prognostic Signature in Lung Adenocarcinoma.

Anran Zhang, Jinpo Yang, Chao Ma, Feng Li, Huan Luo.

   Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Ferroptosis is a newly recognized process of cell death, which is different from other forms of cell death in morphology, biochemistry, and genetics, and has played a vital role in cancer biology. This study aimed to identify a ferroptosis-related gene signature associated with LUAD prognosis.
Methods: Dataset TCGA-LUAD which came from the TCGA portal was taken as the training cohort. GSE72094 and GSE68465 from the GEO database were treated as validation cohorts. Two hundred fifty-nine ferroptosis-related genes were retrieved from the FerrDb database. In the training cohort, Kaplan-Meier and univariate Cox analyses were conducted for preliminary screening of ferroptosis-related genes with potential prognostic capacity. These genes then entered into the LASSO Cox regression model, constructing a gene signature. The latter was then evaluated in the training and validation cohorts via Kaplan-Meier, Cox, and ROC analyses. In addition, the correlations between risk score and autophagy were examined by Pearson correlation coefficient. The analyses of GSEA and immune infiltrating were performed for better studying the function annotation of the gene signature and the character of each kind of immune cells played in the tumor microenvironment.
Results: A 15-gene signature was found from the training cohort and validated by Kaplan-Meier and Cox regression analyses, revealing its independent prognosis value in LUAD. Moreover, the ROC analysis was conducted, confirming a strong predictive ability that this signature owned for LUAD prognosis. One hundred fifty-one of 222 (68.01%) autophagy-related genes were discovered significantly correlated with risk scores. Analyses of GSEA and immune infiltration exhibited in detail the specific pathways that associate with the 15-gene signature and identified the crucial roles of resting mast cells and resting dendritic cells owned in the prognosis of the 15-gene signature.
Conclusion: In this present study, a novel ferroptosis-related 15-gene signature (RELA, ACSL3, YWHAE, EIF2S1, CISD1, DDIT4, RRM2, PANX1, TLR4, ARNTL, LPIN1, HERPUD1, NCOA4, PEBP1, and GLS2) was built. It could accurately predict the prognosis of LUAD and was related to resting mast cells and resting dendritic cells, which provide potential for the personalized outcome prediction and the development of new therapies in LUAD population.

Keywords:  biomarkers; ferroptosis; gene signature; lung adenocarcinoma; prognosis; risk score; tumor immunity

DOI:  https://doi.org/10.3389/fcell.2021.616271