bims-meluca 2022-11-06 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–11–06
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

HPGDS is a novel prognostic marker associated with lipid metabolism and aggressiveness in lung adenocarcinoma.
Serum untargeted metabolomics reveal metabolic alteration of non-small cell lung cancer and refine disease detection.
The correlation of serum sPD-1 and sPD-L1 levels with clinical, pathological characteristics and lymph node metastasis in nonsmall cell lung cancer patients.
Predictors of Survival to Immunotherapy and Chemoimmunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis.
Differential expression of immune-regulatory proteins C5AR1, CLEC4A and NLRP3 on peripheral blood mononuclear cells in early-stage non-small cell lung cancer patients.
Clinical implications of the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in progression and treatment of non-small cell lung cancer.
Integrated single-cell and transcriptome sequencing analyses determines a chromatin regulator-based signature for evaluating prognosis in lung adenocarcinoma.

Front Oncol. 2022 ;12 894485

HPGDS is a novel prognostic marker associated with lipid metabolism and aggressiveness in lung adenocarcinoma.

Fengling Shao, Huajie Mao, Tengling Luo, Qijun Li, Lei Xu, Yajun Xie.

   Background: Lung adenocarcinoma (LUAD) is the most common respiratory globallywith a poor prognosis. Lipid metabolism is extremely important for the occurrence and development of cancer. However, the role of genes involved in lipid metabolism in LUAD development is unclear. We aimed to identify the abnormal lipid metabolism pathway of LUAD, construct a novel prognostic model of LUAD, and discover novel biomarkers involved in lipid metabolism in LUAD.
Methods: Based on differentially expressed genes involved in lipid metabolism in LUAD samples from The Cancer Genome Atlas (TCGA), abnormal lipid metabolism pathways in LUAD were analyzed. The lasso penalized regression analysis was performed on the TCGA cohort (training set) to construct a risk score formula. The predictive ability of the risk score was validated in the Gene Expression Omnibus (GEO) dataset (validation set) using Kaplan-Meier analysis and ROC curves. Finally, based on CRISPR gene editing technology, hematopoietic prostaglandin D synthase (HPGDS) was knocked out in A549 cell lines, the changes in lipid metabolism-related markers were detected by western blotting, and the changes in cell migration were detected by transwell assay.
Results: Based on the differential genes between lung cancer tissue and normal tissue, we found that the arachidonic acid metabolism pathway is an abnormal lipid metabolism pathway in both lung adenocarcinoma and lung squamous cell carcinoma. Based on the sample information of TCGA and abnormally expressed lipid metabolism-related genes, a 9-gene prognostic risk score was successfully constructed and validated in the GEO dataset. Finally, we found that knockdown of HPGDS in A549 cell lines promoted lipid synthesis and is more invasive than in control cells. Rescue assays showed that ACSL1 knockdown reversed the pro-migration effects of HPGDS knockdown. The knockdown of HPGDS promoted migration response by upregulating the expression of the lipid metabolism key enzymes ACSL1 and ACC.
Conclusion: The genes involved in lipid metabolism are associated with the occurrence and development of LUAD. HPGDS can be a therapeutic target of a potential lipid metabolism pathway in LUAD, and the therapeutic target of lipid metabolism genes in LUAD should be studied further.

Keywords:  bioinformatics; biomarkers; hPGDS; lipid metabolism; lung adenocarcinoma

DOI:  https://doi.org/10.3389/fonc.2022.894485
Cancer Sci. 2022 Oct 30.

Serum untargeted metabolomics reveal metabolic alteration of non-small cell lung cancer and refine disease detection.

Jiaoyuan Li, Ke Liu, Zhi Ji, Yi Wang, Tongxin Yin, Tingting Long, Ying Shen, Liming Cheng.

  This study was performed to characterize the metabolic alteration of non-small cell lung cancer (NSCLC) and discover blood-based metabolic biomarkers relevant to lung cancer detection. An untargeted metabolomics-based approach was applied in a case-control study with 193 NSCLC patients and 243 healthy controls. Serum metabolomics were determined by using an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. We screened differential metabolites based on univariate and multivariate analysis, followed by identification of the metabolites and related pathways. For NSCLC detection, machine learning was employed to develop and validate the model based on the altered serum metabolite features. The serum metabolic pattern of NSCLC was definitely different from healthy condition. A total of 278 altered features were found in serum of NSCLC patients comparing with healthy people. About one fifth of the abundant differential features were identified successfully. The altered metabolites were enriched in metabolic pathways such as phenylalanine metabolism, linoleic acid metabolism, and biosynthesis of bile acids. We demonstrated a panel of 10 metabolic biomarkers which representing excellent discriminating capability for NSCLC discrimination, with a combined area under the curve (AUC) in the validation set of 0.95 (95%CI: 0.91-0.98). Moreover, this model showed a desirable performance for the detection of NSCLC in an early stage (AUC = 0.95, 95%CI: 0.92-0.97). Our study offers a perspective on NSCLC metabolic alteration. The finding of the biomarkers might shed light on the clinical detection of lung cancer, especially for those cancers in an early stage in Chinese population.

Keywords:  biomarker; diagnosis; machine learning; metabolomics; non-small cell lung cancer

DOI:  https://doi.org/10.1111/cas.15629
Turk J Med Sci. 2022 Aug;52(4): 1050-1057

The correlation of serum sPD-1 and sPD-L1 levels with clinical, pathological characteristics and lymph node metastasis in nonsmall cell lung cancer patients.

Burcu Ancın, Mesut Melih Özercan, Yiğit Melih Yılmaz, Serkan Uysal, Ulaş Kumbasar, Zeynep Sarıbaş, Erkan Dikmen, Rıza Doğan, Metin Demircin.

   BACKGROUND: Significant advances have been achieved in immunotherapy for the treatment of lung cancer. It is known that tumor cells and cells in the tumor microenvironment express high amounts of programmed cell death ligand 1 (PD-L1). These PD-L1s interact with programmed cell death protein 1 (PD-1), causing immunosuppression. The aim of our study is to examine the correlation between the serum sPD-1 and sPD-L1 levels and clinicopathological characteristics in patients with nonsmall cell lung cancer. We also compared our results with the healthy population (control group).
METHODS: Thirthy-seven nonsmall cell lung cancer (NSCLC) patients who were operated in our clinic were included in our study. The control group included fifteen healthy patients. The sPD-1 and sPD-L1 levels were measured in serum samples by using the ELISA method.
RESULTS: The preoperative sPD-1 and sPD-L1 levels were significantly higher in the study group compared to the control group (44.12 ± 22.25 pg/mL vs. 18.54 ± 6.56 pg/mL; p = 0.001 and 26.15 ± 18.03 pg/mL vs. 10.29 ± 3.08 pg/mL; p = 0.001, respectively). There was a statistically significant decline in serum sPD-1 and sPD-L1 levels at the preoperative and postoperative 1st, 7th, and 30th days following surgical resection (44.12 ± 22.25 pg/mL, 37.86 ± 18.02 pg/mL, 36.33 ± 18.36 pg/mL, 34.14 ± 13.71 pg/mL; p = 0.007 and 26.15 ± 18.03 pg/mL, 20.60 ± 15.50 pg/mL, 18.31 ± 14.04 pg/mL, 13.64 ± 10.60 pg/mL; p = 0.001, respectively).There was a positive correlation between the preoperative and postoperative 30th day serum sPD-1 levels and the tumor size (p = 0.031, r = 0.352; p = 0.024, r = 0.371; respectively). We also found a positive correlation between the preoperative and postoperative 30th day serum sPD-L1 levels and pleural invasion (p = 0.001, p = 0.001; respectively), and the N category (p = 0.015, p = 0.013; respectively).
DISCUSSION: We think that sPD-1 and sPD-L1 levels may be used as a potential biomarker for lung cancer screening, prediction of the stage, and besides to detect recurrences and/or metastases following resection in NSCLC following validation with multicenter and larger-scale prospective trials.

Keywords:  Nonsmall cell lung cancer (NSCLC); soluble programmed cell death ligand 1 (sPD-L1); soluble programmed cell death protein 1 (sPD-1); thoracic surgery

DOI:  https://doi.org/10.55730/1300-0144.5407
J Natl Cancer Inst. 2022 Nov 02. pii: djac205. [Epub ahead of print]

Predictors of Survival to Immunotherapy and Chemoimmunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis.

Alessandro Di Federico, Andrea De Giglio, Francesco Gelsomino, Francesca Sperandi, Barbara Melotti, Andrea Ardizzoni.

   BACKGROUND: many patients with non-small cell lung cancer (NSCLC) derive poor benefit from immunotherapy (IO). For some of them, adding chemotherapy (CT) can improve the outcomes, but the reliability of PD-L1 expression as the only biomarker to distinguish these patients is unsatisfactory. We sought to detect clinicopathological and molecular predictive factors of survival that might be added to PD-L1 expression in the selection of patients that should receive IO alone or chemoimmunotherapy (CIT).
METHODS: We conducted a systematic search of randomized controlled clinical trials (RCT) investigating IO, alone or plus CT, versus CT alone in treatment-naïve advanced NSCLC patients. Meta-analyses and meta-regression analyses were performed to investigate IO alone versus CT, CIT versus CT, and IO alone versus CIT.
RESULTS: 14367 patients with advanced NSCLC across 25 RCT were included. Squamous histology, male sex, current/former smoker status, PD-L1 expression ≥50%, and high tumor mutational burden (TMB) correlated with improved survival with IO alone compared to CT. Conversely, female sex, no smoking history, negative PD-L1 expression, and low TMB correlated with unsatisfactory outcomes with IO alone versus CT, but not with CIT versus CT. CIT improved survival versus IO alone in female patients, never smokers, in those having a PD-L1 expression ≥1% (but not with PD-L1 ≥50%) or a low TMB, and in patients with central nervous system metastasis.
CONCLUSION: these findings suggest some clinicopathological and molecular features that, added to PD-L1 expression, could help in the selection of the most appropriate first-line IO-based treatment for advanced NSCLC patients.

Keywords:  KEAP1; KRAS; PD-L1; STK11; TMB; chemoimmunotherapy; first line; immunotherapy; meta-analysis; non-small cell lung cancer

DOI:  https://doi.org/10.1093/jnci/djac205
Sci Rep. 2022 Nov 02. 12(1): 18439

Differential expression of immune-regulatory proteins C5AR1, CLEC4A and NLRP3 on peripheral blood mononuclear cells in early-stage non-small cell lung cancer patients.

Nussara Pakvisal, Pornrat Kongkavitoon, Chirawadee Sathitruangsak, Nopporn Pornpattanarak, Piyaporn Boonsirikamchai, Pongsakorn Ouwongprayoon, Chatchawit Aporntewan, Poonchavist Chantranuwatana, Apiwat Mutirangura, Chanida Vinayanuwattikun.

Changes in gene expression profiling of peripheral blood mononuclear cells (PBMC) appear to represent the host's response to the cancer cells via paracrine signaling. We speculated that protein expression on circulating T-lymphocytes represent T-lymphocyte trafficking before infiltration into the tumor microenvironment. The possibility of using protein expression on circulating T-lymphocytes as a biomarker to discriminate early-stage non-small cell lung cancer (NSCLC) was explored. Four independent PBMC gene expression microarray datasets (GSE12771, GSE13255, GSE20189 and GSE3934) were analyzed. We selected C5AR1, CLEC4A and NLRP3 based on their significant protein expression in tumor-infiltrating lymphocytes, but not in normal lymphoid tissue. A validation study using automated flow cytometry was conducted in 141 study participants including 76 treatment-naive early-stage non-small cell lung cancer patients (NSCLC), 12 individuals with non-malignant pulmonary diseases, and 53 healthy individuals. Median ratios of C5AR1, CLEC4A and NLRP3 specific antibody staining to CD3 positive cells in early-stage NSCLC patients compared to healthy controls were 0.014 [0-0.37] vs. 0.01 [0-0.07, p = 0.13], 0.03 [0-0.87] vs. 0.02 [0-0.13, p = 0.10] and 0.19 [0-0.60] vs. 0.09 [0.02-0.31, p < 0.0001], respectively. Median fluorescence intensity (MFI) of CD3+C5AR1+, CD3+CLEC4A+ and CD3+NLRP3+ expression in early-stage NSCLC patients compared to healthy volunteers was 185 [64.2-4801] vs. 107.5 [27-229, p < 0.0001], 91.2 [42.4-2355] vs. 71.25 [46.2-103, p = 0.0005], and 1585 [478-5224] vs. 758.5 [318-1976, p < 0.0001], respectively. NLRP3:CD3 ratio, CD3+C5AR1+, CD3+CLEC4A+ and CD3+NLRP3+ MFI were significantly higher in early-stage NSCLC than healthy volunteers with an area under the ROC curve of 0.69-0.76. The CD3+NLRP3+ MFI provided the most distinguishable expression at 71.5% sensitivity and 70% specificity. Furthermore, CD3+NLRP3+ MFI potentially discriminated between early-stage NSCLC from malignant-mimic inflammation and infection pulmonary disease. Further validation in various pulmonary inflammatory disease might be warranted. Our proof-of-principle findings strengthen the hypothesis that malignancies generate distinctive protein expression fingerprints on circulating T-lymphocytes.

DOI: https://doi.org/10.1038/s41598-022-21891-0
J Cancer. 2022 ;13(13): 3434-3443

Clinical implications of the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in progression and treatment of non-small cell lung cancer.

Zihan Quan, Yang Yang, Hongmei Zheng, Yuting Zhan, Jiadi Luo, Yue Ning, Songqing Fan.

  The discovery of immune checkpoints has been well known to provide novel clues for cancer treatments. Immunotherapy against the programmed cell death protein-1 (PD-1) /programmed death-ligand-1 (PD-L1), one of the most popular auxiliary treatments in recent years, has been applied in various tumor treatments, including non-small cell lung cancer (NSCLC). However, inevitable issues such as side effects and drug resistance emerge following the use of immune checkpoint inhibitors. The PI3K/AKT/mTOR pathway may participate in the regulation of PD-L1 expression. Abnormal PI3K/AKT/mTOR pathway activation results in increased PD-L1 protein translation, whereas PD-L1 overexpression can activate the PI3K/AKT/mTOR pathway inversely. Via downstream proteins, including 4E-BP1, STAT3, NF-κB, c-MYC, and AMPK in aberrant energy status, the PI3K/AKT/mTOR pathway can regulate PD-L1 post-transcription and translation. Besides, the regulation of the PI3K pathway by the PD-1/PD-L1 axis involves both tumor cells and the tumor immune microenvironment. Inhibitors targeting the PD-1/PD-L1 have been successfully applied in the treatment of gastrointestinal cancer and breast cancer. Meanwhile, drug resistance from alternative pathway activation also evidently affects clinical progress. To achieve a better therapeutic effect and quality of survival, the combination of multiple treatment modalities presents great research value. Here we reviewed the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in the progression and treatment of NSCLC and summarized its clinical implications. The intracellular interactions between PD-1/PD-L1 and the PI3K/AKT/mTOR pathway indicate that PD-1/PD-L1 inhibitors have a wide range of potential applications. And we presented the mechanism for combining therapy with monoclonal antibody PD-1/PD-L1 and PI3K/AKT/mTOR inhibitors in this review, to broaden the therapies for NSCLC.

Keywords:  Inhibitors; PD-1/PD-L1; PI3K/AKT/mTOR pathway; immunotherapy

DOI:  https://doi.org/10.7150/jca.77619
Front Oncol. 2022 ;12 1031728

Integrated single-cell and transcriptome sequencing analyses determines a chromatin regulator-based signature for evaluating prognosis in lung adenocarcinoma.

Qingtong Shi, Song Han, Xiong Liu, Saijian Wang, Haitao Ma.

   Background: Accumulating evidence has highlighted the significance of chromatin regulator (CR) in pathogenesis and progression of cancer. However, the prognostic role of CRs in LUAD remains obscure. We aim to detect the prognostic value of CRs in LUAD and create favorable signature for assessing prognosis and clinical value of LUAD patients.
Methods: The mRNA sequencing data and clinical information were obtained from TCGA and GEO databases. Gene consensus clustering analysis was utilized to determine the molecular subtype of LUAD. Cox regression methods were employed to set up the CRs-based signature (CRBS) for evaluating survival rate in LUAD. Biological function and signaling pathways were identified by KEGG and GSEA analyses. In addition, we calculated the infiltration level of immunocyte by CIBERSORT algorithm. The expressions of model hub genes were detected in LUAD cell lines by real-time polymerase chain reaction (PCR).
Results: KEGG analysis suggested the CRs were mainly involved in histone modification, nuclear division and DNA modification. Consensus clustering analysis identified a novel CRs-associated subtype which divided the combined LUAD cohort into two clusters (C1 = 217 and C2 = 296). We noticed that a remarkable discrepancy in survival rate among two clusters. Then, a total of 120 differentially expressed CRs were enrolled into stepwise Cox analyses. Four hub CRs (CBX7, HMGA2, NPAS2 and PRC1) were selected to create a risk signature which could accurately forecast patient outcomes and differentiate patient risk. GSEA unearthed that mTORC1 pathway, PI3K/Akt/mTOR and p53 pathway were greatly enriched in CRBS-high cohort. Moreover, the infiltration percentages of macrophage M0, macrophage M2, resting NK cells, memory B cells, dendritic cells and mast cells were statistically significantly different in the two groups. PCR assay confirmed the differential expression of four model biomarkers.
Conclusions: Altogether, our project developed a robust risk signature based on CRs and offered novel insights into individualized treatment for LUAD cases.

Keywords:  chromatin regulator; immune microenvironment; lung adenocarcinoma; prognosis; risk signature

DOI:  https://doi.org/10.3389/fonc.2022.1031728