bims-meluca 2022-10-23 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–10–23
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Associations between body mass index, weight loss and overall survival in patients with advanced lung cancer.
Prognostic Value of GIMAP4 and Its Role in Promoting Immune Cell Infiltration into Tumor Microenvironment of Lung Adenocarcinoma.
Identification of a novel m5C/m6A-related gene signature for predicting prognosis and immunotherapy efficacy in lung adenocarcinoma.
Downregulation of SLC14A1 Expression Indicates Poor Prognosis and Promotes the Progression of Non-Small Cell Lung Cancer.
IGFBP3 inhibits tumor growth and invasion of lung cancer cells and is associated with improved survival in lung cancer patients.
Peripheral T cell cytotoxicity predicts the efficacy of anti-PD-1 therapy for advanced non-small cell lung cancer patients.
The prognostic and immune infiltration role of ITGB superfamily members in non-small cell lung cancer.

J Cachexia Sarcopenia Muscle. 2022 Oct 20.

Associations between body mass index, weight loss and overall survival in patients with advanced lung cancer.

Cameron Oswalt, Yingzhou Liu, Herbert Pang, Jennifer Le-Rademacher, Xiaofei Wang, Jeffrey Crawford.

   BACKGROUND: Weight loss (WL) has been associated with shorter survival in patients with advanced cancer, while obesity has been associated with longer survival. Integrating body mass index (BMI) and WL provides a powerful prognostic tool but has not been well-studied in lung cancer patients, particularly in the setting of clinical trials.
METHODS: We analysed patient data (n = 10 128) from 63 National Cancer Institute sponsored advanced non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) trials. Risk matrices were created using BMI and WL percentage, which were divided into 'grades' based on median survival. Relationships between survival, BMI and WL percentage were examined using Kaplan-Meier estimators and Cox proportional hazards (PH) models with restricted cubic splines.
RESULTS: For NSCLC, a twofold difference was noted in median survival between the BMI > 28 and WL ≤ 5% group (13.5 months) compared with the BMI < 20 and WL > 5% group (6.6 months). These associations were less pronounced in SCLC. Kaplan-Meier curves showed significant survival differences between grades for both NSCLC and SCLC (log-rank, P < 0.0001). In Stage IV NSCLC, Cox PH analyses with restricted cubic splines demonstrated significant associations between BMI and survival in both WL ≤ 5% (P = 0.0004) and >5% (P = 0.0129) groups, as well as in WL > 5% in Stage III (P = 0.0306). In SCLC, these relationships were more complex.
CONCLUSIONS: BMI and WL have strong associations with overall survival in patients with advanced lung cancer, with a greater impact seen in NSCLC compared with SCLC. The integration of a BMI/WL grading scale may provide additional prognostic information and should be included in the evaluation of therapeutic interventions in future clinical trials in advanced lung cancer.

Keywords:  BMI; body composition; lung cancer; weight loss

DOI:  https://doi.org/10.1002/jcsm.13095
Biomed Res Int. 2022 ;2022 7440189

Prognostic Value of GIMAP4 and Its Role in Promoting Immune Cell Infiltration into Tumor Microenvironment of Lung Adenocarcinoma.

Siyuan Chen, Dong Tian, Lauren Petersen, Shuchang Cao, Zachary Quinn, Junyan Kan, Mingfeng Zheng, Wenjun Mao, Yuan Wan.

GIMAPs are recognized as an important regulator in the carcinogenesis and development of lung cancer, but the function of GIMAP4 in the tumor microenvironment (TME) of lung cancers is unclear. In this study, we investigated the expression and variation of GIMAP4 in lung adenocarcinoma (LUAD), to explore its association with infiltration of immune cells. The Cancer Genome Atlas (TCGA) data and Gene Expression Omnibus (GEO) data were analyzed. Infiltration of immune cells was identified with TIMER (Tumor Immune Estimation Resource) and TISIDB (an integrated repository portal for tumor-immune system interactions). GIMAP4 expression declined in non-small-cell lung cancer (NSCLC), correlated with a poor overall survival (OS) in LUAD, indicating that GIMAP4 was a promising prognostic biomarker in LUAD. GIMAP4 mutation frequency was 1.76% in TCGA cohort and was relevant to the expression of immune components. TIMER and CIBERSORT analysis further confirmed that high GIMAP4 expression possibly promoted immune cell infiltration into the TME, with low GIMAP4 impairing the efficacy of immunotherapies targeting common immune check point inhibitors (ICI). GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were performed to provide insights into biological processes involved in LUAD. GIMAP4 was expected to be a prognostic biomarker in LUAD and provides potential adjuvant or neoadjuvant therapeutic strategies for targeting ICIs.

DOI: https://doi.org/10.1155/2022/7440189
Front Genet. 2022 ;13 990623

Identification of a novel m5C/m6A-related gene signature for predicting prognosis and immunotherapy efficacy in lung adenocarcinoma.

Yiming Ma, Jun Yang, Tiantai Ji, Fengyun Wen.

  Lung adenocarcinoma (LUAD) is the most prevalent subtype of non-small cell lung cancer (NSCLC) and is associated with high mortality rates. However, effective methods to guide clinical therapeutic strategies for LUAD are still lacking. The goals of this study were to analyze the relationship between an m5C/m6A-related signature and LUAD and construct a novel model for evaluating prognosis and predicting drug resistance and immunotherapy efficacy. We obtained data from LUAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Based on the differentially expressed m5C/m6A-related genes, we identified distinct m5C/m6A-related modification subtypes in LUAD by unsupervised clustering and compared the differences in functions and pathways between different clusters. In addition, a risk model was constructed using multivariate Cox regression analysis based on prognostic m5C/m6A-related genes to predict prognosis and immunotherapy response. We showed the landscape of 36 m5C/m6A regulators in TCGA-LUAD samples and identified 29 differentially expressed m5C/m6A regulators between the normal and LUAD groups. Two m5C/m6A-related subtypes were identified in 29 genes. Compared to cluster 2, cluster 1 had lower m5C/m6A regulator expression, higher OS (overall survival), higher immune activity, and an abundance of infiltrating immune cells. Four m5C/m6A-related gene signatures consisting of HNRNPA2B1, IGF2BP2, NSUN4, and ALYREF were used to construct a prognostic risk model, and the high-risk group had a worse prognosis, higher immune checkpoint expression, and tumor mutational burden (TMB). In patients treated with immunotherapy, samples with high-risk scores had higher expression of immune checkpoint genes and better immunotherapeutic efficacy than those with low-risk scores. We concluded that the m5C/m6A regulator-related risk model could serve as an effective prognostic biomarker and predict the therapeutic sensitivity of chemotherapy and immunotherapy.

Keywords:  LUAD; RNA methylation; drug sensitivity; immunotherapy; prognosis

DOI:  https://doi.org/10.3389/fgene.2022.990623
Ann Clin Lab Sci. 2022 Sep;52(5): 753-762

Downregulation of SLC14A1 Expression Indicates Poor Prognosis and Promotes the Progression of Non-Small Cell Lung Cancer.

Yunfeng Zhou, Yang Yuan, Qiangnu Zhang, Yi Shen, Wei Chen, Lesen Yan.

OBJECTIVE: Solute carrier (SLC) genes are known to be involved in the development of human tumors. Here, we identified a group of non-small cell lung cancer (NSCLC) - associated SLC genes and explored the role and potential mechanism of action for SLC14A1 in NSCLC.
METHODS: We used public NSCLC gene expression databases to select NSCLC-associated SLC genes. A Cox proportional risk model was used to estimate the hazard rate of selected NSCLC-associated SLC genes. SLC14A1 was selected as a candidate for further study. The expression and effect on survival of SLC14A1 in multiple NSCLC datasets were investigated. The expression of SLC14A1 was modulated in Calu-6 and A549 cells by transfection and a series of proliferation and migration assays were performed. Parameters related to glycolysis and HK2 expression were detected after transfection.
RESULTS: Fourteen SLC genes were identified as NSCLC-related SLC genes. Among them, SLC14A1 was downregulated in tumor tissues in multiple datasets. Low expression of SLC14A1 was indicative of poor prognosis in NSCLC. Knockdown of SLC14A1 promoted proliferation and migration in Calu-6 cells. Overexpression of SLC14A1 showed the opposite effect in A549 cells. Additionally, SLC14A1 changes were associated with glycolysis. This was demonstrated by HK2 mRNA and protein levels being regulated by SLC14A1.
CONCLUSIONS: In our study SLC14A1 suppressed the proliferation and migration of NSCLC cell lines Calu-6 and A549 and was associated with glycolysis. Therefore, SLC14A1 may be a diagnostic marker or therapeutic target for NSCLC patients.

Keywords: Glycolysis; HK2; NSCLC; SLC14A1; Solute carrier
Transl Oncol. 2022 Oct 17. pii: S1936-5233(22)00225-X. [Epub ahead of print]27 101566

IGFBP3 inhibits tumor growth and invasion of lung cancer cells and is associated with improved survival in lung cancer patients.

Hartmut Kuhn, Armin Frille, Marie Anna Petersen, Jonas Oberhuber-Kurth, Lukas Hofmann, Albrecht Gläser, Sabine Taubenheim, Sabine Klagges, Sebastian Kraemer, Johannes Broschewitz, Maximilian von Laffert, Hubert Wirtz.

The insulin-like growth factor (IGF)-pathway is involved in tumor cell proliferation, metastasis, and survival. We aimed to find out what effects IGF binding protein 3 (IGFBP3) exerted on H1299 lung cancer (LC) cells in terms of tumor growth and invasion and whether IGFBP3 was associated with clinical and pathological parameters in a prospective cohort of LC patients. H1299 cells were transfected with an IGFBP3-expressing vector. Its influence on apoptosis induction via flow cytometry annexin V FITC assay, cell proliferation in 2D and 3D cell culture, and invasion were examined. Expression of several matrix metalloproteinases (MMPs) and inhibitors (TIMP-1) were also investigated in IGFBP3-transfected LC cells. Further, data on LC patients (n = 131), tumor characteristics, and survival were prospectively collected and correlated with IGFBP3 plasma levels. IGFBP3 did not influence apoptosis induction and 2D cell proliferation. However, both spheroid growth (3D proliferation) and invasion of IGFBP3-transfected cells planted in an extracellular matrix-based gel were significantly inhibited. IGFBP3 inhibited MMP-1 release, and the total MMP activity. In LC patients, higher IGFBP3 plasma levels correlated with both lower clinical tumor stage, grading, Ki-67 staining, and the absence of necrosis (P < 0.05, respectively). Increased IGFBP3 plasma levels were associated with improved overall survival (hazard ratio 0.37, P = 0.01). In conclusion, overexpressed IGFBP3 in a LC cell line inhibited tumor growth and invasion. Translating from bench to bedside, investigation of clinicopathological parameters confirmed these experimental results showing that higher IGFBP3 plasma levels were associated with less aggressive tumor growth, reduced tumor spread, and improved survival of LC patients.

DOI: https://doi.org/10.1016/j.tranon.2022.101566
Sci Rep. 2022 Oct 19. 12(1): 17461

Peripheral T cell cytotoxicity predicts the efficacy of anti-PD-1 therapy for advanced non-small cell lung cancer patients.

Kota Iwahori, Takeshi Uenami, Yukihiro Yano, Toshihiko Ueda, Mari Tone, Yujiro Naito, Yasuhiko Suga, Kiyoharu Fukushima, Takayuki Shiroyama, Kotaro Miyake, Shohei Koyama, Haruhiko Hirata, Izumi Nagatomo, Hiroshi Kida, Masahide Mori, Yoshito Takeda, Atsushi Kumanogoh, Hisashi Wada.

Anti-programmed cell death-1 (PD-1) therapy exerts beneficial effects in a limited population of cancer patients. Therefore, more accurate diagnostics to predict the efficacy of anti-PD-1 therapy are desired. The present study investigated whether peripheral T cell cytotoxicity predicts the efficacy of anti-PD-1 therapy for advanced non-small cell lung cancer (NSCLC) patients. Advanced NSCLC patients treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) were consecutively enrolled in the present study. Peripheral blood samples were subjected to an analysis of peripheral T cell cytotoxicity and flow cytometry prior to the initiation of anti-PD-1 therapy. Peripheral T cell cytotoxicity was assessed using bispecific T-cell engager (BiTE) technology. We found that progression-free survival was significantly longer in patients with high peripheral T cell cytotoxicity (p = 0.0094). In the multivariate analysis, treatment line and peripheral T cell cytotoxicity were independent prognostic factors for progression-free survival. The analysis of T cell profiles revealed that peripheral T cell cytotoxicity correlated with the ratio of the effector memory population in CD4+ or CD8+ T cells. Furthermore, the results of flow cytometry showed that the peripheral CD45RA+CD25+/CD4+ T cell ratio was higher in patients with than in those without severe adverse events (p = 0.0076). These results indicated that the peripheral T cell cytotoxicity predicted the efficacy of anti-PD-1 therapy for advanced NSCLC patients.

DOI: https://doi.org/10.1038/s41598-022-22356-0
Am J Transl Res. 2022 ;14(9): 6445-6466

The prognostic and immune infiltration role of ITGB superfamily members in non-small cell lung cancer.

Juan Wu, Wenjun Wang, Zhouhua Li, Xiaoqun Ye.

PURPOSE: We aimed to explore the prognostic value of integrin-β superfamily members (ITGBs) and their role in immune cell infiltration in non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: Study cases were acquired from The Cancer Genome Atlas database and The Human Protein Atlas. We then used R package and several online tools to analyze and visualize the roles of ITGBs in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).
RESULTS: We found that ITGBs were differentially expressed in NSCLC. In LUAD, high expression of ITGB1 and ITGB4 was an independent risk factor for poor prognosis, and ITGB7 was an independent protective factor for overall survival; in LUSC, high expression of ITGB1, 3, 5, and 6 was associated with poor prognosis, and ITGB8 was an independent protective factor for disease-specific survival. Protein-protein interaction networks for the most associated co-expressed genes revealed the following target genes of ITGBs: PTPRC, ITGAM, and ITGB2 in LUAD and FN1, PTPRC, and ITGB2 in LUSC. Gene ontology analysis revealed that functions related to adhesion, junction, and binding were highly enriched in LUAD and LUSC. ITGBs were significantly associated with immune cell infiltration and the expression of immunomodulation-related genes in LUAD and LUSC.
CONCLUSION: ITGBs were differentially expressed in NSCLC. ITGB1, 4, and 7 and ITGB1, 3, 5, 6, and 8 were found as prognostic markers in LUAD and LUSC, respectively. ITGBs were significantly associated with immune cell infiltration and the expression of immunomodulation-related genes.

Keywords: ITGBs; LUAD; LUSC; NSCLC; immune infiltration; prognosis