bims-meluca 2020-06-28 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2020–06–28
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth.
Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation.
NRF2-Driven KEAP1 Transcription in Human Lung Cancer.
Role that anorexia and weight loss play in patients with stage IV lung cancer.
Folate receptor-positive circulating tumor cells as a predictive biomarker for the efficacy of first-line pemetrexed-based chemotherapy in patients with non-squamous non-small cell lung cancer.
PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma.
Association between diabetes mellitus and lung cancer: meta-analysis.

Elife. 2020 Jun 23. pii: e53618. [Epub ahead of print]9

Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth.

Caroline Contat, Pierre-Benoit Ancey, Nadine Zangger, Silvia Sabatino, Justine Pascual, Stéphane Escrig, Louise Jensen, Christine Goepfert, Bernard Lanz, Mario Lepore, Rolf Gruetter, Anouk Rossier, Sabina Berezowska, Christina Neppl, Inti Zlobec, Stéphanie Clerc-Rosset, Graham William Knott, Jeffrey C Rathmell, E Dale Abel, Anders Meibom, Etienne Meylan.

  Glucose utilization increases in tumors, a metabolic process that is observed clinically by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). However, is increased glucose uptake important for tumor cells, and which transporters are implicated in vivo? In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss diminishes tumor development. 18F-FDG-PET analyses of tumors demonstrate that Glut1 and Glut3 loss decreases glucose uptake, which is mainly dependent on Glut1. Using 13C-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS) and electron microscopy, we also report the presence of lamellar body-like organelles in tumor cells accumulating glucose-derived biomass, depending partially on Glut1. Our results demonstrate the requirement for two glucose transporters in lung adenocarcinoma, the dual blockade of which could reach therapeutic responses not achieved by individual targeting.

Keywords:  NanoSIMS; cancer biology; genetically engineered mouse model of cancer; glucose transporters; human; lamellar bodies; lung adenocarcinoma; mouse

DOI:  https://doi.org/10.7554/eLife.53618
Cell Commun Signal. 2020 Jun 23. 18(1): 98

Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation.

Meiling Gong, Yan Li, Xiaoping Ye, Linlin Zhang, Zhifang Wang, Xiaowen Xu, Yejing Shen, Cuixia Zheng.

   BACKGROUND AND PURPOSE: Targeted therapy and immunotherapy have led to dramatic change in the treatment of lung cancer, however, the overall 5-year survival rate of lung cancer patients is still suboptimal. It is important to exploit new potential of molecularly targeted therapies. High-frequency somatic mutations in KEAP1/NRF2 (27.9%) have been identified in lung squamous cell carcinoma. In this research, we explored the role of KEAP1 somatic mutations in the development of LSCC and whether a nuclear factor erythroid 2-related factor 2(NRF2) inhibitor be potential to target lung cancer carrying KEAP1/NRF2 mutations.
METHODS: Lung cancer cell lines A549 and H460 with loss-of-function mutations in KEAP1 stably transfected with wild-type (WT) KEAP1 or somatic mutations in KEAP1 were used to investigate the functions of somatic mutations in KEAP1. Flow cytometry, plate clone formation experiments, and scratch tests were used to examine reactive oxygen species, proliferation, and migration of these cell lines.
RESULTS: The expression of NRF2 and its target genes increased, and tumor cell proliferation, migration, and tumor growth were accelerated in A549 and H460 cells stably transfected with KEAP1 mutants compared to control cells with a loss-of-function KEAP1 mutation and stably transfected with WT KEAP1 in both in vitro and in vivo studies. The proliferation of A549 cell line trasfected with the R320Q KEAP1 mutant was inhibited more apparent than that of the A549 cell line trasfected with WT KEAP1 after treatment with NRF2 inhibitor ML385.
CONCLUSION: Somatic mutations of KEAP1 identified from patients with LSCC likely promote tumorigenesis mediated by activation of the KEAP1/NRF2 antioxidant stress response pathway. NRF2 inhibition with ML385 could inhibit the proliferation of tumor cells with KEAP1 mutation. Video abstract.

Keywords:  KEAP1/NRF2; Lung carcinoma; NRF2 inhibitor; Somatic mutation; Targeted therapy

DOI:  https://doi.org/10.1186/s12964-020-00568-z
Mol Cancer Res. 2020 Jun 22. pii: molcanres.0108.2020. [Epub ahead of print]

NRF2-Driven KEAP1 Transcription in Human Lung Cancer.

Yijun Tian, Qian Liu, Shengnan Yu, Qian Chu, Yuan Chen, Kongming Wu, Liang Wang.

Constitutive NRF2 activation by disrupted KEAP1-NRF2 interaction has been reported in a variety of human cancers. However, studies focusing on NRF2-driven KEAP1 expression under human cancer contexts are still uncommon. We examined mRNA expression correlation between NRF2 and KEAP1 in multiple human cancers. We measured KEAP1 mRNA and protein alterations in response to the activation or silencing of NRF2. We queried ChIP-seq datasets to identify NRF2 binding to KEAP1 promoters in human cells. We used reporter assay and CRISPR editing to assess KEAP1 promoter activity and mRNA abundance change. To determine specimen implication of the feedback pattern, we used gene expression ratio to predict NRF2 signal disruption as well as patients' prognosis. Correlation analysis showed KEAP1 mRNA expression was in positive association with NRF2 in multiple squamous cell cancers. The positive correlations were consistent across all squamous cell lung cancer cohorts, but not in adenocarcinomas. In human lung cells, NRF2 interventions significantly altered KEAP1 mRNA and protein expressions. ChIP-qPCR and sequencing data demonstrated consistent NRF2 occupancy to KEAP1 promoter. Deleting NRF2 binding site significantly reduced baseline and inducible KEAP1 promoter activity and KEAP1 mRNA expression. By incorporating tumor tissue KEAP1 mRNA expressions in estimating NRF2 signaling disruptions, we found increased TXN/KEAP1 mRNA ratio in cases with NRF2 gain or KEAP1 loss and decreased NRF2/KEAP1 mRNA ratio in cases with NRF2-KEAP1 somatic mutations. In TCGA PanCancer datasets, we also identified that cases with loss-of-function mutations in NRF2 pathway recurrently appeared above the NRF2-KEAP1 mRNA expression regression lines. Moreover, compared with previous NRF2 signatures, the ratio-based strategy showed better predictive performance in survival analysis with multiple SQC cohort validations. Implications: NRF2-driven KEAP1 transcription is a crucial component of NRF2 signaling modulation. This hidden circuit will provide in-depth insight into novel cancer prevention and therapeutic strategies.

DOI: https://doi.org/10.1158/1541-7786.MCR-20-0108
J Bras Pneumol. 2020 ;pii: S1806-37132020000400207. [Epub ahead of print]46(4): e20190420

Role that anorexia and weight loss play in patients with stage IV lung cancer.

Juliana Pereira Franceschini, Sergio Jamnik, Ilka Lopes Santoro.

OBJECTIVE: To evaluate the prevalence of anorexia and weight loss at diagnosis (pre-treatment), to identify the factors associated with pre-treatment weight loss, and to determine the prognostic role of anorexia and weight loss in the overall survival of patients with stage IV lung cancer.
METHODS: This was a retrospective observational cohort study. The patients were stratified by the presence/absence of anorexia and of pre-treatment weight loss, which generated a measure composed of four categories, which were the independent variables.
RESULTS: Among the 552 patients included in the study, anorexia and pre-treatment weight loss were present in 39.1% and 70.1%, respectively. After adjusting for age, male gender, and Karnofsky performance status, we found that anorexia and tumor size were significantly associated with pre-treatment weight loss. In a Cox multivariate analysis, adjusted for age, male gender and low Karnofsky performance status were found to be independent predictors of worse survival, as was concomitance of anorexia and weight loss.
CONCLUSIONS: Anorexia and pre-treatment weight loss appear to be relevant problems in the follow-up of patients with advanced (stage IV) lung cancer Specific interventions are of crucial importance in individualized treatment plans, even within the context of palliative care.

DOI: https://doi.org/10.36416/1806-3756/e20190420
Ann Transl Med. 2020 May;8(10): 631

Folate receptor-positive circulating tumor cells as a predictive biomarker for the efficacy of first-line pemetrexed-based chemotherapy in patients with non-squamous non-small cell lung cancer.

Xiaoxia Chen, Fei Zhou, Xuefei Li, Guohua Yang, Chao Zhao, Wei Li, Fenying Wu, Jia Yu, Guanghui Gao, Jiayu Li, Aiwu Li, Shengxiang Ren, Caicun Zhou.

   Background: There is a lack of well-established biomarkers to predict the efficacy of pemetrexed-based chemotherapy. In this prospective phase II study, we investigated the correlation of folate receptor (FR)-positive circulating tumor cell (CTC) level with the clinical outcomes of patients with advanced non-squamous non-small cell lung cancer (nsNSCLC) when treated with pemetrexed-based chemotherapy.
Methods: A total of 98 nsNSCLC patients were enrolled. Peripheral blood was collected from each patient prior to initiation of treatment. FR-positive CTCs were enriched by immunomagnetic leukocyte depletion and quantified using ligand-targeted polymerase chain reaction (LT-PCR) method.
Results: Patients with relatively low CTC level (11-16 FU/3 mL, n=32) showed a significantly shorter progression-free survival (PFS) and overall survival (OS) compared with those in the "high CTC level group" (>16 FU/3mL, n=28; median PFS, 133 versus 320 days, P<0.001; median OS, 632 days versus "not reached", P=0.003). Patients in the "high CTC level group" also achieved superior objective response rate (ORR) and disease control rate (DCR) over those in the "low CTC level group" (ORR, 40.9% versus 9.5%, P=0.0339; DCR, 100% versus 81.0%, P=0.0485). The clinical outcomes of pemetrexed in the "negative-CTC group" (<11 FU/3mL, n=38) fell between the "high CTC level group" and the "low CTC level group" (median PFS, 290 days; median OS, 1,122 days; ORR: 21.2%, DCR: 93.9%). Further multivariate Cox proportional hazards regression analysis demonstrated that "high CTC level" was an independent factor that was significantly associated with better PFS [hazard ratio (HR) =0.26, 95% confidence interval (CI), 0.12-0.58, P=0.001] and OS (HR =0.23, 95% CI, 0.06-0.92, P=0.037).
Conclusions: Our results implied that FR-positive CTC is a promising biomarker to predict the clinical outcome of pemetrexed-based chemotherapy in patients with advanced nsNSCLC.

Keywords:  Biomarkers; circulating tumor cells (CTCs); folate receptor (FR); non-squamous non-small cell lung cancer (nsNSCLC); pemetrexed

DOI:  https://doi.org/10.21037/atm-19-4680
PPAR Res. 2020 ;2020 2510951

PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma.

Shunbin Shi, Guiping Yu, Bin Huang, Yedong Mi, Yan Kang, Julia Pia Simon.

Previous studies showed that PPAR-gamma (PPARG) ligands might serve as potential therapeutic agents for nonsmall cell lung cancer (NSCLC). However, a few studies reported the specific relationship between PPARG and lung squamous cell carcinoma (LSCC). Here, we made an effort to explore the relationship between PPARG and LSCC. First, we used mega-analysis and partial mega-analysis to analyze the effects of PPARG on LSCC by using 12 independent LSCC expression datasets (285 healthy controls and 375 LSCC cases). Then, literature-based molecular pathways between PPARG and LSCC were established. After that, a gene set enrichment analysis (GSEA) was conducted to study the functionalities of PPARG and PPARG-driven triggers within the molecular pathways. Finally, another mega-analysis was constructed to test the expression changes of PPARG and its driven targets. The partial mega-analysis showed a significant downregulated expression of PPARG in LSCC (LFC = -1.08, p value = 0.00073). Twelve diagnostic markers and four prognostic markers were identified within multiple PPARG-LSCC regulatory pathways. Our results suggested that the activation of PPARG expression may inhibit the development and progression of LSCC through the regulation of LSCC upstream regulators and downstream marker genes, which were involved in tumor cell proliferation and protein polyubiquitination/ubiquitination.

DOI: https://doi.org/10.1155/2020/2510951
Eur J Clin Invest. 2020 Jun 26. e13332

Association between diabetes mellitus and lung cancer: meta-analysis.

Zi-Han Yi, Yannick Luther Agbana, Guo-Hang Xiong, Yue-Li Ni, Fang Yun, Jing Chen, Zhe Yang, Qiao Zhang, Ying-Min Kuang, Yue-Chun Zhu.

   BACKGROUND: This study aimed to summarize the association between diabetes mellitus (DM) and the incidence of lung cancer using a meta-analysis of cohort studies.
MATERIALS AND METHODS: We systematically searched PubMed, Embase, and the Cochrane Library to identify potential cohort studies. Relative risk (RR) was used to calculate the association between DM and the risk of lung cancer. Subgroup analysis, sensitivity analysis, and test for publication bias were performed. Twenty cohort studies were selected.
RESULTS: The participants with DM showed little or no significant effect on the risk of lung cancer (RR: 1.10; 95% CI: 0.99-1.23; P=0.087). DM was not associated with the risk of lung cancer in men (RR: 1.11; 95%CI: 0.92-1.35; P=0.270), but a significant association was observed in women (RR: 1.18; 95%CI: 1.10-1.28; P<0.001). Subgroup analysis suggested that smoker status were confounding variables that could bias the relationship between DM and the incidence of lung cancer.
CONCLUSIONS: This meta-analysis suggests that DM has no significant impact on the incidence of lung cancer in men but has a harmful effect on women.

Keywords:  cohort studies; diabetes mellitus; lung cancer; meta-analysis; risk

DOI:  https://doi.org/10.1111/eci.13332