bims-meluca Biomed news
on Metabolism of non-small cell lung carcinoma
Issue of 2018‒11‒18
eight papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Sci Transl Med. 2018 Nov 14. pii: eaat5933. [Epub ahead of print]10(467):
    Scafoglio CR, Villegas B, Abdelhady G, Bailey ST, Liu J, Shirali AS, Wallace WD, Magyar CE, Grogan TR, Elashoff D, Walser T, Yanagawa J, Aberle DR, Barrio JR, Dubinett SM, Shackelford DB.
      The diagnostic definition of indeterminate lung nodules as malignant or benign poses a major challenge for clinicians. We discovered a potential marker, the sodium-dependent glucose transporter 2 (SGLT2), whose activity identified metabolically active lung premalignancy and early-stage lung adenocarcinoma (LADC). We found that SGLT2 is expressed early in lung tumorigenesis and is found specifically in premalignant lesions and well-differentiated adenocarcinomas. SGLT2 activity could be detected in vivo by positron emission tomography (PET) with the tracer methyl 4-deoxy-4-[18F] fluoro-alpha-d-glucopyranoside (Me4FDG), which specifically detects SGLT activity. Using a combination of immunohistochemistry and Me4FDG PET, we identified high expression and functional activity of SGLT2 in lung premalignancy and early-stage/low-grade LADC. Furthermore, selective targeting of SGLT2 with FDA-approved small-molecule inhibitors, the gliflozins, greatly reduced tumor growth and prolonged survival in autochthonous mouse models and patient-derived xenografts of LADC. Targeting SGLT2 in lung tumors may intercept lung cancer progression at early stages of development by pairing Me4FDG PET imaging with therapy using SGLT2 inhibitors.
    DOI:  https://doi.org/10.1126/scitranslmed.aat5933
  2. Cell Metab. 2018 Nov 05. pii: S1550-4131(18)30637-5. [Epub ahead of print]
    Eichner LJ, Brun SN, Herzig S, Young NP, Curtis SD, Shackelford DB, Shokhirev MN, Leblanc M, Vera LI, Hutchins A, Ross DS, Shaw RJ, Svensson RU.
      AMPK, a conserved sensor of low cellular energy, can either repress or promote tumor growth depending on the context. However, no studies have examined AMPK function in autochthonous genetic mouse models of epithelial cancer. Here, we examine the role of AMPK in murine KrasG12D-mediated non-small-cell lung cancer (NSCLC), a cancer type in humans that harbors frequent inactivating mutations in the LKB1 tumor suppressor-the predominant upstream activating kinase of AMPK and 12 related kinases. Unlike LKB1 deletion, AMPK deletion in KrasG12D lung tumors did not accelerate lung tumor growth. Moreover, deletion of AMPK in KrasG12D p53f/f tumors reduced lung tumor burden. We identified a critical role for AMPK in regulating lysosomal gene expression through the Tfe3 transcription factor, which was required to support NSCLC growth. Thus, AMPK supports the growth of KrasG12D-dependent lung cancer through the induction of lysosomes, highlighting an unrecognized liability of NSCLC.
    Keywords:  AMPK; Kras; LKB1; Tfe3; Tfeb; cancer; lung; lysosomes; metabolism; tumor
    DOI:  https://doi.org/10.1016/j.cmet.2018.10.005
  3. Int J Oncol. 2018 Nov 06.
    Chen L, Zhou Y, Tang X, Yang C, Tian Y, Xie R, Chen T, Yang J, Jing M, Chen F, Wang C, Sun H, Huang Y.
      [18F]fluoro‑2‑deoxyglucose (FDG) positron emission tomography (PET)‑computed tomography (CT) is a functional imaging modality based on glucose metabolism. The association between the maximum standardized uptake value (SUVmax) from 18F‑FDG PET‑CT scanning and epidermal growth factor receptor (EGFR) mutation status has, to the best of our knowledge, not previously been fully elucidated, and the potential mechanisms by which EGFR mutations alter FDG uptake are largely unknown. A total of 157 patients who were pathologically diagnosed with non‑small cell lung cancer (NSCLC) who underwent EGFR mutation testing and PET‑CT pretreatment between June 2015 and October 2017 were retrospectively analyzed. χ2 and univariate analyses were performed to identify the contributors to EGFR mutation. The receiver operating characteristic (ROC) curve was analyzed, and the area under the curve (AUC) was calculated. Glucose transporter 1 (GLUT1) and NADPH oxidase 4 (NOX4) expression, and reactive oxygen species (ROS) activity were detected in the A549 (wild‑type), PC‑9 (EGFR mutation‑positive, EGFR exon 19del) and NCI‑H1975 (EGFR mutation‑positive, combined with L858R and T790M substitution) cell lines. A total of 109 patients who met the criteria were enrolled, and 63 of those tested as EGFR mutation‑positive. The SUVmax values were significantly lower in patients with EGFR mutations (mean, 6.52±0.38) compared with in patients with wild‑type EGFR (mean, 9.37±0.31; P<0.001). Using univariate analysis, EGFR mutation status was significantly associated with sex, smoking status, tumor histology and SUVmax of the primary tumor. In the multivariate analysis, smoking status (never‑smoking), histopathology (adenocarcinoma) and SUVmax (≤9.91) were the statistically significant predictors of EGFR mutations. ROC curve analysis identified that the SUVmax cut‑off point was 9.92, for which the AUC was 0.75 (95% confidence interval, 0.68‑0.83). Reverse transcription‑polymerase chain reaction indicated that the GLUT1 mRNA decreased in the PC‑9 and NCI‑H1975 cell lines compared with the A549 cell line (0.82±0.07 and 0.72±0.04 vs. 0.98±0.04, respectively; P<0.05) and decreased ROS activity was observed in the PC‑9 cell line. Furthermore, the expression of NOX4 mRNA decreased by 20% in PC‑9 (P<0.01) and by 14% (P<0.05) in NCI‑H1975 cells. In addition, NOX4 protein expression decreased by 13% in PC‑9 and by 16% in NCI‑H1975 cells (both P<0.05) compared with the A549 cell line. The SUVmax could be considered to effectively predict EGFR mutation status of patients with NSCLC, and the EGFR mutation status may alter FDG uptake partially via the NOX4/ROS/GLUT1 axis.
    DOI:  https://doi.org/10.3892/ijo.2018.4626
  4. Biochimie. 2018 Nov 12. pii: S0300-9084(18)30323-7. [Epub ahead of print]
    Callejón-Leblic B, Pereira-Vega A, Vazquez-Gandullo E, Sánchez-Ramos JL, Gómez-Ariza JL, García-Barrera T.
      The high prevalence of lung cancer (LC) has triggered the search of biomarkers for early diagnosis of this disease. For this purpose the study of metabolic changes related to the development of lung cancer could provide interesting information about its early diagnosis. In this sense, chronic obstructive pulmonary disease (COPD), a disease associated with tumor development, is a comorbidity that increases the risk of onset and progression of lung neoplasia and has also to be considered in the study of pathology related to lung cancer. This work develop a metabolomic approach based on direct infusion mass spectrometry using a hybrid triple quadrupole-time of flight mass spectrometer (DI-ESI-QqQ-TOF-MS) in order to identify altered metabolites from serum of LC and COPD patients and evaluate its relationship and implication in the progression of LC. This methodology has been applied to 30 serum samples from LC, 30 healthy patients used as controls (HC) and 30 serum samples from COPD to found altered metabolites from both LC and COPD diseases. In addition, some metabolic differences and similarities were found in Pulmonary Emphysema and Chronic Bronchitis patients. On the other hand, altered metabolites were studied in different stages of LC (II, III and IV) to evaluate the perturbation of them throughout the progression of disease. The sample treatment consisted of the extraction of polar and non-polar metabolites from serum that was later infused into the mass spectrometer using an electrospray ionization source in positive and negative mode. Partial least squares discriminant analysis (PLS-DA) allowed a classification between LC, HC and COPD groups in all acquisition modes. A total of 35 altered and common metabolites between LC and COPD, including amino acids, fatty acids, lysophospholipids, phospholipids and triacylglycerides were identified, being alanine, aspartate and glutamate metabolism the most altered. Finally, ROC curves were applied to the dataset and metabolites with AUC value higher than 0.70 were considered as relevant in the progression of LC.
    Keywords:  Chronic Obstructive Pulmonary Disease; Direct infusion; Lung cancer; Mass spectrometry; Metabolomic fingerprinting; Serum
    DOI:  https://doi.org/10.1016/j.biochi.2018.11.007
  5. J Natl Cancer Inst. 2018 Nov 13.
    Yang R, Li SW, Chen Z, Zhou X, Ni W, Fu DA, Lu J, Kaye FJ, Wu L.
      Background: The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs.Methods: INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided.
    Results: INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival.
    Conclusions: LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.
    DOI:  https://doi.org/10.1093/jnci/djy166
  6. Cancer Gene Ther. 2018 Nov 12.
    De A, Jacobson BA, Peterson MS, Stelzner ME, Jay-Dixon J, Kratzke MG, Patel MR, Bitterman PB, Kratzke RA.
      Hyperactivation of eIF4F-mediated translation occurs in many if not all cancers. As a consequence, cancer cells aberrantly enhance expression of malignancy-related proteins that are involved in cell cycle progression, angiogenesis, growth, and proliferation. With this in mind eIF4F is a promising molecular target for therapeutics that counteract pathological eIF4F activity. Here we used 4EGI-1, a small-molecule inhibitor of cap-mediated translation that disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex to treat non-small cell lung cancer (NSCLC). Treatment of cells with 4EGI-1 reduced cell proliferation, decreased cap-dependent complex formation, induced apoptosis, enhanced sensitivity to gemcitabine, and altered global cellular translation. Suppression of cap-dependent translation by 4EGI-1 resulted in diminished expression of oncogenic proteins c-Myc, Bcl-2, cyclin D1, and survivin, whereas β-actin expression was left unchanged. In light of these results, small-molecule inhibitors like 4EGI-1 alone or with chemotherapy should be further evaluated in the treatment of NSCLC.
    DOI:  https://doi.org/10.1038/s41417-018-0058-6
  7. Radiographics. 2018 Nov-Dec;38(7):38(7): 2134-2149
    Kandathil A, Kay FU, Butt YM, Wachsmann JW, Subramaniam RM.
      Lung cancer is the leading cause of cancer-related mortality in the United States, and accurate staging plays a vital role in determining prognosis and treatment. The recently revised eighth edition of the TNM staging system for lung cancer defines new T and M descriptors and updates stage groupings on the basis of substantial differences in survival. There are new T descriptors that are based on the findings at histopathologic examination, and T descriptors are reassigned on the basis of tumor size and extent. No changes were made to the N descriptors in the eighth edition of the TNM staging of lung cancer, because the four N categories that are based on the location of the diseased nodes can be used to consistently predict prognosis. The eighth edition includes a new M1b descriptor for patients with a single extrathoracic metastatic lesion in a single organ (M1b), because they have better survival and different treatment options, compared with those with multiple extrathoracic lesions (M1c). Examination with fluorine 18 fluorodeoxyglucose (FDG) PET/CT is the standard of care and is an integral part of the clinical staging of patients with lung cancer. To provide the treating physicians with accurate staging information, radiologists and nuclear medicine physicians should be aware of the updated classification system and should be cognizant of the site-specific strengths and limitations of FDG PET/CT. In this article, the eighth edition of the TNM staging system is reviewed, as well as the role of FDG PET/CT in the staging of non-small cell lung carcinoma. ©RSNA, 2018.
    DOI:  https://doi.org/10.1148/rg.2018180060
  8. Eur J Nucl Med Mol Imaging. 2018 Nov 10.
    Ho KC, Toh CH, Li SH, Liu CY, Yang CT, Lu YJ, Su TP, Wang CW, Yen TC.
      PURPOSE: The role of brain FDG-PET in patients with lung cancer and brain metastases remains unclear. Here, we sought to determine the prognostic significance of whole-body PET/CT plus brain PET/MR in predicting the time to neurological progression (nTTP) and overall survival (OS) in this patient group.METHODS: Of 802 patients with non-small cell lung cancer who underwent primary staging by a single-day protocol of whole-body PET/CT plus brain PET/MR, 72 cases with adenocarcinoma and brain metastases were enrolled for a prognostic analysis of OS. On the basis of the available follow-up brain status, only 52 patients were eligible for prognostic analysis of nTTP. Metastatic brain tumors were identified on post-contrast MR imaging, and the tumor-to-brain ratio (TBR) was measured on PET images.
    RESULTS: Multivariate analysis revealed that FDG-PET findings and eligibility for initial treatment with targeted therapy were significant independent predictors of nTTP and OS. A new index, termed the molecular imaging prognostic (MIP) score, was proposed to define three disease classes. MIP scores were significant predictors of both nTTP and OS (P < 0.001). Pre-existing prognostic indices such as Lung-molGPA scores were significant predictors of OS but did not predict nTTP.
    CONCLUSIONS: When staging is performed with whole-body PET/CT plus brain PET/MR, our new prognostic index may be helpful to stratify the outcomes of patients with lung adenocarcinoma and brain metastases. The superior prognostic power of this index for nTTP might be used to select appropriate patients for intracranial control and thereby achieve better quality of life.
    Keywords:  Brain metastasis; Lung adenocarcinoma; PET/CT; PET/MR
    DOI:  https://doi.org/10.1007/s00259-018-4210-1