bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2020‒04‒19
ten papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Cancer Immunol Immunother. 2020 Apr 16.
    Mitchell KG, Amini B, Wang Y, Carter BW, Godoy MCB, Parra ER, Behrens C, Villalobos P, Reuben A, Lee JJ, Weissferdt A, Moran CA, Fujimoto J, Sepesi B, Walsh GL, Vaporciyan AA, Hofstetter WL, William WN, Gibbons DL, Wang J, Hwu P, Swisher SG, Piwnica-Worms D, Kadara H, Wistuba II, Heymach JV, Peng W, Cascone T.
      Enhanced tumor glycolytic activity is a mechanism by which tumors induce an immunosuppressive environment to resist adoptive T cell therapy; therefore, methods of assessing intratumoral glycolytic activity are of considerable clinical interest. In this study, we characterized the relationships among tumor 18F-fluorodeoxyglucose (FDG) retention, tumor metabolic and immune phenotypes, and survival in patients with resected non-small cell lung cancer (NSCLC). We retrospectively analyzed tumor preoperative positron emission tomography (PET) 18F-FDG uptake in 59 resected NSCLCs and investigated correlations between PET parameters (SUVMax, SUVTotal, SUVMean, TLG), tumor expression of glycolysis- and immune-related genes, and tumor-associated immune cell densities that were quantified by immunohistochemistry. Tumor glycolysis-associated immune gene signatures were analyzed for associations with survival outcomes. We found that each 18F-FDG PET parameter was positively correlated with tumor expression of glycolysis-related genes. Elevated 18F-FDG SUVMax was more discriminatory of glycolysis-associated changes in tumor immune phenotypes than other 18F-FDG PET parameters. Increased SUVMax was associated with multiple immune factors characteristic of an immunosuppressive and poorly immune infiltrated tumor microenvironment, including elevated PD-L1 expression, reduced CD57+ cell density, and increased T cell exhaustion gene signature. Elevated SUVMax identified immune-related transcriptomic signatures that were associated with enhanced tumor glycolytic gene expression and poor clinical outcomes. Our results suggest that 18F-FDG SUVMax has potential value as a noninvasive, clinical indicator of tumor immunometabolic phenotypes in patients with resectable NSCLC and warrants investigation as a potential predictor of therapeutic response to immune-based treatment strategies.
    Keywords:  Positron emission tomography; Resected non-small cell lung cancer; Tumor glycolysis; Tumor immunometabolic phenotypes
  2. Cell Death Dis. 2020 Apr 17. 11(4): 242
    Wang Y, Guo S, Li D, Tang Y, Li L, Su L, Liu X.
      Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer, and the identification of the apoptotic process of NSCLC is vital for its treatment. Usually, both the expression level and the cell surface level of TNFRSF10B (TNF Receptor superfamily member 10B) will increase after treatment with some chemotherapeutic agents, which plays a critical role in the apoptosis induction. However, the exact molecular mechanism underlying TNFRSF10B regulation remains largely elusive. Here, we found that TNFRSF10B, along with a vesicular trafficking regulator protein, YIPF2, were upregulated after treatment with pemetrexed (PEM) in NSCLC cells. Besides, YIPF2 increased the surface level of TNFRF10B, while YIPF2 knockdown inhibited the upregulation of TNFRSF10B and its recycling to plasma membrane. In addition, RAB8 decreased the cell surface TNFRSF10B by promoting its removing from plasma membrane to cytoplasm. Furthermore, we found that YIPF2, RAB8 and TNFRSF10B proteins interacted physically with each other. YIPF2 could further inhibit the physical interaction between TNFRSF10B and RAB8, thereby suppressing the removing of TNFRSF10B from plasma membrane to cytoplasm mediated by RAB8 and maintaining its high level on cell surface. Finally, using bioinformatics database, the YIPF2-TNFRSF10B axis was confirmed to be associated with the malignant progression of lung cancer. Taken together, we show that YIPF2 promotes chemotherapeutic agent-mediated apoptosis via enhancing TNFRSF10B recycling to plasma membrane in NSCLC cells. These findings may be beneficial for the development of potential prognostic markers of NSCLC and may provide effective treatment strategy.
  3. Biochem Pharmacol. 2020 Apr 13. pii: S0006-2952(20)30188-X. [Epub ahead of print] 113960
    Feng J, Jiang W, Liu Y, Huang W, Hu K, Li K, Chen J, Ma C, Sun Z, Pang X.
      Signal transducer and activator of transcription 3 (STAT3) exerts a profound role in regulating mitochondrial function and cellular metabolism. Mitochondrial STAT3 supports RAS-dependent malignant transformation and tumor growth. However, whether pharmacological blockade of STAT3 leads to metabolic lethality in KRAS-mutant lung cancer remains unclear. Pyrvinium pamoate, a clinical antihelminthic drug, preferentially inhibited the growth of KRAS-mutant lung cancer cells in vitro and in vivo. Mechanistic study revealed that pyrvinium dose-dependently suppressed STAT3 phosphorylation at tyrosine 705 and serine 727. Overexpression mitochondrial STAT3 prominently weakened the therapeutic efficacy of pyrvinium. As a result of targeting STAT3, pyrvinium selectively triggered reactive oxygen species release, depolarized mitochondrial membrane potential and suppressed aerobic glycolysis in KRAS-mutant lung cancer cells. Importantly, the cytotoxic effects of pyrvinium could be significantly augmented by glucose deprivation both in vitro and in a patient-derived lung cancer xenograft mouse model in vivo. The combined efficacy significantly correlated with intratumoural STAT3 suppression. Our findings reveal that KRAS-mutant lung cancer cells are vulnerable to STAT3 inhibition exerted by pyrvinium, providing a promising direction for developing therapies targeting STAT3 and metabolic synthetic lethality for the treatment of KRAS-mutant lung cancer.
    Keywords:  KRAS; Metabolism; Pyrvinium pamoate; STAT3; Synthetic lethality
  4. Chem Res Toxicol. 2020 Apr 15.
    Dator R, Villalta PW, Thomson N, Jensen J, Hatsukami DK, Stepanov I, Warth B, Balbo S.
      African American (AA) smokers are at a higher risk of developing lung cancer compared to Whites. The variations in the metabolism of nicotine and tobacco-derived carcinogens in these groups were reported previously with the levels of nicotine metabolites and carcinogen-derived metabolites measured using targeted approaches. While useful, these targeted strategies are not able to detect global metabolic changes for use in predicting the detrimental effects of tobacco use and ultimately lung cancer susceptibility among smokers. To address this limitation, we have performed global untargeted metabolomics profiling in urine of AA and White smokers to characterize the pattern of metabolites, identify differentially regulated pathways, and correlate these profiles with the observed variations in lung cancer risk between these two populations. Urine samples from AA (n=30) and White (n=30) smokers were used for metabolomics analysis acquired in both positive and negative electrospray ionization modes. LC-MS data were uploaded onto the cloud-based XCMS Online ( platform for retention time correction, alignment, feature detection, annotation, statistical analysis, data visualization, and automated systems biology pathway analysis. The latter identified global differences in the metabolic pathways in the two groups including the metabolism of carbohydrates, amino acids, nucleotides, fatty acids, and nicotine. Significant differences in the nicotine degradation pathway (cotinine glucuronidation) in the two groups were observed and confirmed using a targeted LC-MS/MS approach. These results are consistent with previous studies demonstrating AA smokers with lower glucuronidation capacity compared to Whites. Furthermore, the D-glucuronate degradation pathway was found to be significantly different between the two populations, with lower amounts of the putative metabolites detected in AA compared to Whites. We hypothesize that the differential regulation of the D-glucuronate degradation pathway is a consequence of the variations in the glucuronidation capacity observed in the two groups. Other pathways including the metabolism of amino acids, nucleic acids, and fatty acids were also identified, however, the biological relevance and implications of these differences across ethnic groups need further investigation. Overall, the applied metabolomics approach revealed global differences in the metabolic networks and endogenous metabolites in AA and Whites, which could be used and validated as new potential panel of biomarkers that could be used to predict lung cancer susceptibility among smokers in population-based studies.
  5. Clin Lung Cancer. 2020 Mar 12. pii: S1525-7304(20)30075-9. [Epub ahead of print]
    Shukla NA, Yan MN, Hanna N.
      The treatment of advanced non-small-lung cancer (NSCLC) has steadily evolved over the past 2 decades, and current therapy includes chemoimmunotherapy or targeted therapy with tyrosine kinase inhibitors (TKIs). Angiogenesis inhibitors were first approved in the mid-2000s in combination with chemotherapy for the treatment of NSCLC. The addition of anti-angiogenics to chemotherapy resulted in modest increases in survival when median overall survival was less than 1 year. More recently, the use of anti-angiogenics has fallen out of favor with the advent of checkpoint inhibitors and never-before-seen durable long-term responses. However, we postulate that there is still an important role for anti-angiogenics in this era of targeted therapy and checkpoint inhibitors in the treatment of NSCLC. Preclinical studies have shown that combination blockade of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways leads to synergistic antitumor effects. These results have been replicated in the clinical setting in patients who harbor EGFR mutations, with VEGF inhibitor-TKI dual therapy leading to impressive survival outcomes. Similarly, combination treatment with checkpoint inhibitors and VEGF inhibitors have led to unprecedented survival outcomes in both advanced renal cell cancer as well as NSCLC. In this review, we explore the evolution of anti-angiogenic therapy in advanced NSCLC and discuss the clinical efficacy of angiogenesis inhibitors in combination with chemotherapy, TKI therapy, and checkpoint inhibitors.
    Keywords:  Anti-angiogenic agents; EGFR inhibitors; Immunotherapy; Targeted therapy; VEGF inhibitors
  6. Mol Cell Biochem. 2020 Apr 15.
    Wang C, Xu J, Yuan D, Bai Y, Pan Y, Zhang J, Shao C.
      Lung cancer has been recognized as the leading cause of cancer-related death worldwide. Despite the improvements of treatment, the distant metastasis and recurrence of lung cancer caused by therapy resistance is the biggest challenge in clinical management. Extracellular vesicles named exosomes play crucial roles in intercellular communication as signaling mediators and are involved in tumor development. In this study, we isolated exosomes from irradiated lung cancer cells and co-cultured the exosomes with other lung cancer cells. It was found that cellular growth and motility of recipient cells were facilitated. High-throughput LC-MS/MS assay of exosomal proteins and Gene Ontology enrichment analyses indicated that the metabolic enzymes ALDOA and ALDH3A1 had potential contribution in exosome-enhanced motility of recipient cells, and clinical survival analysis demonstrated the close correlations between ALDOA or ALDH3A1 expression and poor prognosis of lung cancer patients. After co-culturing with exosomes derived from irradiated cancer cells, the expressions of these metabolic enzymes were elevated and the glycolytic activity was promoted in recipient cancer cells. In conclusion, our data suggested that exosomes from irradiated lung cancer cells regulated the motility of recipient cells by accelerating glycolytic process, where exosomal ALDOA and ALDH3A1 proteins were important signaling factors.
    Keywords:  Cell motility; Exosomes; Glycolytic proteins; Lung cancer cells; Radiation
  7. Sci Rep. 2020 Apr 14. 10(1): 6380
    Frederick M, Skinner HD, Kazi SA, Sikora AG, Sandulache VC.
      Mitochondrial activity is a critical component of tumor metabolism, with profound implications for tumorigenesis and treatment response. We analyzed clinical, genomic and expression data from patients with oral cavity squamous cell carcinoma (OCSCC) in order to map metabologenomic events which may correlate with clinical outcomes and identified nuclear genes involved in oxidative phosphorylation and glycolysis (OXPHOG) as a critical predictor of patient survival. This correlation was validated in a secondary unrelated set of lung squamous cell carcinoma (LUSC) and was shown to be driven largely by over-expression of nuclear encoded components of the mitochondrial electron transport chain (ETC) coordinated with an increase in tumor mitochondrial DNA copy number and a strong threshold effect on patient survival. OCSCC and LUSC patients with a favorable OXPHOG signature demonstrated a dramatic (>2fold) improvement in survival compared to their counterparts. Differential OXPHOG expression correlated with varying tumor immune infiltrates suggesting that the interaction between tumor metabolic activity and tumor associated immunocytes may be a critical driver of improved clinical outcomes in this patient subset. These data provide strong support for studies aimed at mechanistically characterizing the interaction between tumor mitochondrial activity and the tumor immune microenvironment.
  8. J Comput Biol. 2020 Apr 16.
    Zhang S, Lu Y, Liu Z, Li X, Wang Z, Cai Z.
      Metabolic genes have been reported to act as crucial roles in tumor progression. Lung adenocarcinoma (LUAD) is one of the most common cancers worldwide. This study aimed to predict the potential mechanism and novel markers of metabolic signature in LUAD. The gene expression profiles and the clinical parameters were obtained from The Cancer Genome Atlas-Lung adenocarcinoma (TCGA-LUAD) and Gene Expression Omnibus data set (GSE72094). A total of 105 differentially expressed metabolic genes of intersect expression in TCGA-LUAD and GSE72094 were screened by R language. Univariate Cox regression model found 18 survival-related genes and then the least absolute shrinkage and selection operator model was successfully constructed. Six significant genes prognostic model was validated though independent prognosis analysis. The model revealed high values for prognostic biomarkers by time-dependent receiver operating characteristic (ROC) analysis, risk score, Heatmap, and nomogram. In addition, Gene Set Enrichment Analysis showed that multiplex metabolism pathways correlated with LUAD. Furthermore, we found the six genes aberrantly expressed in LUAD samples. Our study showed that metabolism pathways play important roles in LUAD progression. The six metabolic genes could predict potential prognostic and diagnostic biomarkers in LUAD.
    Keywords:  GEO; TCGA; lung adenocarcinoma; metabolic gene; prognostic
  9. Cancer Lett. 2020 Apr 11. pii: S0304-3835(20)30184-1. [Epub ahead of print]
    Chen J, Liu A, Lin Z, Wang B, Chai X, Chen S, Lu W, Zheng M, Cao T, Zhong M, Li R, Wu M, Lu Z, Pang W, Huang W, Xiao L, Lin D, Wang Z, Lei F, Chen X, Long W, Zheng Y, Chen Q, Zeng J, Ren D, Li J, Zhang X, Huang Y.
      Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death due to its early recurrence and widespread metastatic potential. Accumulating studies have reported that dysregulation of circadian rhythms-associated regulators is implicated in the recurrence and metastasis of NSCLC. Therefore, identification of metastasis-associated circadian rhythm genes is clinically necessary. Here we report that the circadian gene hepatic leukemia factor (HLF), which was dramatically reduced in early-relapsed NSCLC tissues, was significantly correlated with early progression and distant metastasis in NSCLC patients. Upregulating HLF inhibited, while silencing HLF promoted lung colonization, as well as metastasis of NSCLC cells to bone, liver and brain in vivo. Importantly, downexpression of HLF promoted anaerobic metabolism to support anchorage-independent growth of NSCLC cells under low nutritional condition by activating NF-κB/p65 signaling through disrupting translocation of PPARα and PPARγ. Further investigations revealed that both genetic deletion and methylation contribute to downexpression of HLF in NSCLC tissues. In conclusion, our results shed light on a plausible mechanism by which HLF inhibits distant metastasis in NSCLC, suggesting that HLF may serve as a novel target for clinical intervention in NSCLC.
    Keywords:  NF-κB pathway; NSCLC; PPARα; PPARγ; circadian rhythms regulator; distant metastasis; hepatic leukemia factor (HLF)
  10. Nutr Cancer. 2020 ;72(5): 858-863
    Dong J, Zeng Y, Zhang P, Li C, Chen Y, Li Y, Wang K.
      Objectives: This study aimed to analyze and evaluate serum insulin-like growth factor-binding protein 2 (IGFBP2) levels as a new biomarker of severe malnutrition in patients with advanced lung cancer.Design and methods: This prospective study involved 59 patients with advanced lung cancer. We detected serum IGFBP2 level by using enzyme-linked immunosorbent assay and analyzed its relationship to clinical characteristics, nutritional status, Glasgow prognostic score (GPS), and survival. Serum albumin and C-reactive protein (CRP) levels were measured, and nutritional status was assessed using Patient-Generated Subjective Global Assessment (PG-SGA). The best cutoff point value for serum IGFBP2 level was established using receiver operating characteristic analysis. Kaplan-Meier method was utilized to analyze the survival curves.Results: Serum IGFBP2 levels were elevated in patients with advanced lung cancer and severe malnutrition. The best cutoff value for serum IGFBP2 level was determined at 363 ng/ml, which could diagnose severe malnutrition with 73.3% sensitivity and 70.5% specificity and was found to be related to albumin, CRP, and GPS. Patients whose serum IGFBP2 levels were higher than 363 ng/ml had poor survival outcome.Conclusion: This study demonstrates the remarkably association between higher serum level of IGFBP2 and severe malnutrition, albumin, CRP, GPS, and survival. Hence, serum IGFBP2 level can be used as a potential biomarker for diagnosis of severe malnutrition in patients with advanced lung cancer.