bims-meluca 2019-09-15 papers

Nat Commun. 2019 Sep 13. 10(1): 4190

Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma.

Sarah A Best, Sheryl Ding, Ariena Kersbergen, Xueyi Dong, Ji-Ying Song, Yi Xie, Boris Reljic, Kaiming Li, James E Vince, Vivek Rathi, Gavin M Wright, Matthew E Ritchie, Kate D Sutherland.

The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-of-function mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1-deficient KrasG12D lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells. Keap1 loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers.

DOI: https://doi.org/10.1038/s41467-019-12164-y

Eur J Nucl Med Mol Imaging. 2019 Sep 09.

New insight on the correlation of metabolic status on 18F-FDG PET/CT with immune marker expression in patients with non-small cell lung cancer.

Yang Wang, Ning Zhao, Zhanbo Wu, Na Pan, Xuejie Shen, Ting Liu, Feng Wei, Jian You, Wengui Xu, Xiubao Ren.

BACKGROUND: Metabolic information obtained through 18F-flurodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is used to evaluate malignancy by calculating the glucose uptake rate, and these parameters play important roles in determining the prognosis of non-small cell lung cancer (NSCLC). The expression of immune-related markers in tumor tissue reflects the immune status in the tumor microenvironment. However, there is lack of reports on the association between metabolic variables and intra-tumor immune markers. Herein, we investigate the correlation between metabolic status on 18F-FDG PET/CT and intra-tumor immunomarkers' expression in NSCLC patients.
METHODS: From April 2008 to August 2014, 763 patients were enrolled in the analysis to investigate the role of maximum standardized uptake value (SUVmax) in lung cancer. One hundred twenty-two tumor specimens were analyzed by immunohistochemistry (IHC) to intra-tumor immune cells and programmed death protein ligand 1(PD-L1) expression on tumor cells. The correlation between metabolic variables and the expression of tissue immune markers were analyzed.
RESULTS: SUVmax values have significant variations in different epidermal growth factor receptor (EGFR) statuses (wild type vs mutant type), high/low neutrophil-to-lymphocyte ratio (NLR) groups, and high/low platelets-to-lymphocyte ratio (PLR) groups (p < 0.001, p < 0.001, p = 0.003, respectively). SUVmax was an independent prognostic factor in lung cancer patients (p = 0.013). IHC demonstrated a statistically significant correlation between SUVmax and the expression of CD8 tumor-infiltrating lymphocytes (p = 0.015), CD163 tumor-associated macrophages (TAMs) (p = 0.003), and Foxp3-regulatory T cells (Tregs) (p = 0.004), as well as PD-1 and PD-L1 (p = 0.003 and p = 0.012, respectively). With respect to patient outcomes, disease stage, BMI, SUVmax, metabolic tumor volume (MTV), TLG (tumor lesion glycolysis), CD163-TAMs, CD11c-dendritic cells (DCs), PD-L1, and Tregs showed a statistically significant correlation with progression-free survival (PFS) (p < 0.001, 0.023, < 0.001, 0.007, 0.005, 0.004, 0.008, 0.048, and 0.014, respectively), and disease stage, SUVmax, MTV, TLG, CD163-TAMs, CD11c-DCs, and PD-L1 showed a statistically significant correlation with overall survival (OS) (p < 0.001, < 0.001, 0.014, 0.012, < 0.001, 0.001, and < 0.001, respectively).
CONCLUSION: This study revealed an association between metabolic variable and immune cell expression in the tumor microenvironment and suggests that SUVmax on 18F-FDG PET/CT could be a potential predictor for selecting candidates for immunotherapy.

Keywords: 18F-FDG PET/CT; Immunomarkers; Non-small cell lung cancer; Prognosis; Standardized uptake value

DOI: https://doi.org/10.1007/s00259-019-04500-7

Adv Appl Bioinform Chem. 2019 ;12 15-32

Computational evaluation of natural compounds as potential inhibitors of human PEPCK-M: an alternative for lung cancer therapy.

Luiz Phillippe R Baptista, Vanessa Vc Sinatti, Joao Hm Da Silva, Laurent Emmanuel Dardenne, Ana Carolina Guimarães.

Background: Lung cancer is the leading cause of cancer-related death worldwide. Among its subtypes, non-small cell lung cancer (NSCLC) is the most common. Recently, the mitochondrial isoform of the enzyme phosphoenolpyruvate carboxykinase (HsPEPCK-M) was identified as responsible for the metabolic adaptation in the NSCLC allowing tumor growth even under conditions of glucose deficiency. This adaptation is possible due to the role of HsPEPCK-M in gluconeogenesis, converting the oxaloacetate to phosphoenolpyruvate in the presence of GTP, which plays an important role in the energetic support of these tumors. In this context, it was shown that the inhibition or knockdown of this enzyme was able to induce apoptosis in NSCLC under low glucose conditions.
Purpose: In this study, novel putative inhibitors were proposed for the human PEPCK-M (HsPEPCK-M) based on a computer-aided approach.
Methods: Comparative modeling was used to generate 3D models for HsPEPCK-M. Subsequently, the set of natural compounds of the ZINC database was screened against HsPEPCK-M models using structure-based pharmacophore modeling and molecular docking approaches. The selected compounds were evaluated according to its chemical diversity and clustered based on chemical similarity.
Results: The pharmacophore hypotheses, generated based on known PEPCK inhibitors, were able to select 7,124 candidate compounds. These compounds were submitted to molecular docking studies using three conformations of HsPEPCK-M generated by comparative modeling. The aim was to select compounds with high predicted binding affinity for at least one of the conformations of HsPEPCK-M. After molecular docking, 612 molecules were selected as potential inhibitors of HsPEPCK-M. These compounds were clustered according to their structural similarity. Chemical profiling and binding mode analyses of these compounds allowed the proposal of four promising compounds: ZINC01656421, ZINC895296, ZINC00895535 and ZINC02571340.
Conclusion: These compounds may be considered as potential candidates for HsPEPCK-M inhibitors and may also be used as lead compounds for the development of novel HsPEPCK-M inhibitors.

Keywords: PEPCK-M; lung cancer; molecular docking; natural products; pharmacophore modeling; virtual screening

DOI: https://doi.org/10.2147/AABC.S197119

Carcinogenesis. 2019 Sep 05. pii: bgz152. [Epub ahead of print]

YTH domain family 2 promotes lung cancer cell growth by facilitating 6-phosphogluconate dehydrogenase mRNA translation.

Hao Sheng, Zhen Li, Shixin Su, Wenjing Sun, Xiaoya Zhang, Leilei Li, Jing Li, Shuangping Liu, Bin Lu, Shuai Zhang, Changliang Shan.

N6-methyladenosin (m6A) is one of widespread post-transcriptional mRNA modifications in eukaryotes and the m6A modification plays critical roles in various human cancers. However, the role of m6A-binding proteins in cancer metabolism remains elusive. Here we report that YTH domain family 2 (YTHDF2) is upregulated in lung cancer tissues, promotes lung cancer cell growth, and enhances the pentose phosphate pathway (PPP) flux, which is crucial for tumor growth. Mechanistically, YTHDF2 directly binds to the m6A modification site of 6-phosphogluconate dehydrogenase (6PGD) three prime untranslated region (3'-UTR) to promote 6PGD mRNA translation in lung cancer cells. Collectively, our data indicate that YTHDF2 acts as a tumor promoter to enhance tumor growth via facilitating 6PGD mRNA translation.

Keywords: 6-phosphogluconate dehydrogenase; YTH domain family 2; m6A modification; oxidative pentose phosphate pathway

DOI: https://doi.org/10.1093/carcin/bgz152

Oncol Lett. 2019 Oct;18(4): 3453-3462

Prognostic roles of mitochondrial transcription termination factors in non-small cell lung cancer.

Shuangyan Sun, Chunjiao Wu, Changliang Yang, Jian Chen, Xiu Wang, Yingji Nan, Zhicheng Huang, Lixia Ma.

Mitochondrial transcription termination factors (MTERFs) regulate mitochondrial gene transcription and metabolism in numerous types of cells. Previous studies have indicated that MTERFs serve pivotal roles in the pathogenesis of various cancer types. However, the expression and prognostic roles of MTERFs in patients with non-small cell lung cancer (NSCLC) remain elusive. The present study investigated the gene alteration frequency and expression level using Gene Expression Omnibus datasets and reverse transcription-quantitative polymerase chain reaction, and evaluated the prognostic roles of MTERFs in patients with NSCLC using the Kaplan-Meier plotter database. In human lung cancer tissues, it was observed that the mRNA levels of MTERF1, 2, 3 and 4 were positively associated with the copy number of these genes. The mRNA expression levels of MTERF1 and 3 were significantly increased in NSCLC tissues compared with adjacent non-tumor tissues; however, the mRNA expression of MTERF2 was significantly decreased in NSCLC tissues. High mRNA expression levels of MTERF1, 2, 3 and 4 were strongly associated with an improved overall survival rate (OS) in patients with lung adenocarcinoma. Additionally, high mRNA expression levels of MTERF1, 2, 3 and 4 were also strongly associated with an improved OS of patients with NSCLC in the earlier stages of disease (stage I) or patients with negative surgical margins. These results indicate the critical prognostic values of MTERF expression levels in NSCLC. The findings of the present study may be beneficial for understanding the molecular biology mechanism of NSCLC and for generating effective therapeutic approaches for patients with NSCLC.

Keywords: Kaplan-Meier plotter; mitochondrial transcription termination factor; non-small cell lung cancer; prognostic roles

DOI: https://doi.org/10.3892/ol.2019.10680