bims-meluca 2021-09-12 papers

Cell Death Dis. 2021 Sep 04. 12(9): 832

Notch1/TAZ axis promotes aerobic glycolysis and immune escape in lung cancer.

Oncogenic signaling pathway reprograms cancer cell metabolism to promote aerobic glycolysis in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Notch1 signaling, dysregulated in lung cancer, is correlated with increased glycolysis. Herein, we demonstrate in lung cancer that Notch1 promotes glycolytic gene expression through functional interaction with histone acetyltransferases p300 and pCAF. Notch1 signaling forms a positive feedback loop with TAZ. Notch1 transcriptional activity was increased in the presence of TAZ and the activation was TEAD1 independent. Notably, aerobic glycolysis was critical for Notch1/TAZ axis modulation of lung cancer growth in vitro and in vivo. Increased level of extracellular lactate via Notch1/TAZ axis inhibited cytotoxic T-cell activity, leading to the invasive characteristic of lung cancer cells. Interaction between Notch1 and TAZ promoted aerobic glycolysis and immune escape in lung cancer. Our findings provide potential therapeutic targets against Notch1 and TAZ and would be important for clinical translation in lung cancer.

DOI: https://doi.org/10.1038/s41419-021-04124-6

Bioengineered. 2021 Dec;12(1): 6186-6200

Integrated analysis of hypoxia-associated lncRNA signature to predict prognosis and immune microenvironment of lung adenocarcinoma patients.

Jun Shao, Boqing Zhang, Lin Kuai, Qingguo Li.

Lung adenocarcinoma (LUAD) represents the main lung cancer (LC) subtype that possesses a disappointing clinical outcome over the decades. Tumor hypoxia is closely bound up with dismal survival for malignant tumor cases. We identified hypoxia-associated long non-coding RNA (lncRNA) signature to be an explicit indicator for predicting prognosis. The present work acquired RNA-seq and associated clinical data from The Cancer Genome Atlas (TCGA) database. Consensus cluster analysis characterized the hypoxia status of LUAD patients. Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) method determined significantly prognosis-related lncRNAs which were used to create a prognostic model. Diverse statistical approaches like the Kaplan-Meier curve, receiver operating characteristic (ROC) curve, and nomogram were adopted to verify the accuracy of the risk score. The potential immune environment landscape was unearthed by the CIBERSORT algorithm. Three hypoxia-related clusters were determined and 221 differentially expressed hypoxia-related lncRNAs were screened out. We developed a new predictive model based on seven lncRNAs (LINC00941, AC022784.1, AC079949.2, LINC00707, AL161431.1, AC010980.2 and AC090001.1). Kaplan-Meier curves and ROC plots uncovered the reliable predictive power of the risk score model. In addition, the immunosuppressive landscape was presented in the high-risk group by immune cell infiltration analysis. The seven hypoxia lncRNAs survival signature in our article are robust, accurate tools for predicting overall survival in LUAD patients.

Keywords: Hypoxia; TCGA; lncRNA; lung adenocarcinoma; prognosis; signature

DOI: https://doi.org/10.1080/21655979.2021.1973874

Eur J Cancer. 2021 Sep 06. pii: S0959-8049(21)00528-1. [Epub ahead of print]157 108-113

STK11/LKB1 and KEAP1 mutations in non-small cell lung cancer: Prognostic rather than predictive?

Alessandro Di Federico, Andrea De Giglio, Claudia Parisi, Francesco Gelsomino.

Immune checkpoint inhibitors (ICIs), either alone or combined with chemotherapy, represent the cornerstone of the treatment of advanced non-small cell lung cancer (NSCLC) without targetable gene alterations. Programmed death ligand-1 expression currently represents the only available biomarker to predict response to ICI, although its reliability is debated. However, most patients still do not derive benefit from immunotherapy, making the identification of further predictive biomarkers extremely needed. Serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) and Kelch-like ECH-associated protein 1 (KEAP1) mutations occur in 25-30% and 11-27% of advanced NSCLC, respectively. Several studies associated their presence with poor outcomes in patients treated with ICI. However, more recent evidence showed poor outcomes among NSCLC with STK11/LKB1 and/or KEAP1 mutations regardless of the treatment received. We reviewed the literature to provide a comprehensive, timely and structured overview of the role of STK11/LKB1 and KEAP1 mutations in NSCLC. Although conflicting outcomes have been reported by studies evaluating their impact in KRAS wild-type patients or regardless of KRAS mutation, the correlation between STK11/LKB1 and KEAP1 mutations and poor outcomes with ICI appears to be consistent in presence of concurrent KRAS mutations. The main limitations of most studies are represented by the inclusion of other gene mutations (e.g. TP53) together with STK11 and KEAP1 mutations as a group and by the lack of comparison arms including patients who received other treatments (e.g. chemotherapy). Studies evaluating the impact of STK11 and KEAP1 mutations on the outcomes with ICI and other therapies showed a similar effect regardless of the treatment received, suggesting a prognostic, rather than predictive, value.

Keywords: Immune-checkpoint inhibitors; Immunotherapy; KEAP1; KRAS; Lung cancer; NSCLC; Prognostic; SMARCA4; STK11; TP53

DOI: https://doi.org/10.1016/j.ejca.2021.08.011

Front Mol Biosci. 2021 ;8 706650

Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy.

Caterina Bartolacci, Cristina Andreani, Yasmin El-Gammal, Pier Paolo Scaglioni.

HRAS, NRAS and KRAS, collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer. Oncogenic RAS aberrantly rewires metabolic pathways promoting the generation of intracellular reactive oxygen species (ROS). In particular, lipids have gained increasing attention serving critical biological roles as building blocks for cellular membranes, moieties for post-translational protein modifications, signaling molecules and substrates for ß-oxidation. However, thus far, the understanding of lipid metabolism in cancer has been hampered by the lack of sensitive analytical platforms able to identify and quantify such complex molecules and to assess their metabolic flux in vitro and, even more so, in primary tumors. Similarly, the role of ROS in RAS-driven cancer cells has remained elusive. On the one hand, ROS are beneficial to the development and progression of precancerous lesions, by upregulating survival and growth factor signaling, on the other, they promote accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis. Here, we overview the recent advances in the study of the relation between RAS and lipid metabolism, in the context of different cancer types. In particular, we will focus our attention on how lipids and oxidative stress can either promote or sensitize to ferroptosis RAS driven cancers. Finally, we will explore whether this fine balance could be modulated for therapeutic gain.

Keywords: RAS oncogenes; ferroptosis; lipid metabolism; oxidative stress; tumorigenesis

DOI: https://doi.org/10.3389/fmolb.2021.706650

FEBS Open Bio. 2021 Sep 09.

Construction and analysis of a novel ferroptosis related gene signature predicting prognosis in lung adenocarcinoma.

Jing Zhou, Xinyue Wang, Zhaona Li, Richeng Jiang.

Ferroptosis is a newly discovered, iron-dependent, non-apoptotic form of programmed cell death that plays an important role in the development of lung adenocarcinoma (LUAD). In this study, ferroptosis-related genes (FRGs) were identified from the FerrDb dataset, and the mRNA expression profiles and corresponding clinical data of LUAD patients were downloaded from the University of California, Santa Cruz (UCSC) databases. Data from LUAD patients from the Gene Expression Omnibus (GEO) dataset were used as the verification set. Cox and Lasso regression analysis was used to screen the FRGs with prognostic value, and six prognostic-related FRGs were selected to construct prognostic risk score signatures. Immunohistochemistry was utilized to manifest the differential expression of six FRGs in tumor and normal tissues at the protein level. Functional enrichment analysis indicated that FRGs were mainly enriched in ferroptosis-related pathways. Patients were divided into high- and low-risk groups based on the median risk score. The Kaplan-Meier survival curves confirmed that patients with a high score had significantly worse overall survival. Receiver operating characteristic (ROC) curves proved that the prognostic signature has good sensitivity and specificity for predicting the prognosis of LUAD patients. Nomogram analysis showed that the prognostic signature has potential independent prognostic value. Moreover, the prognostic signature has been shown to be significantly associated with some clinical features (T stage, N stage, tumor stage and survival status) as well as many immune-activity-related genes and immune-checkpoint-related genes. In conclusion, we constructed a prognostic signature consisting of six FGRs, which can provide a reference for predicting the prognosis of LUAD patients.

Keywords: Ferroptosis; Lung adenocarcinoma; Overall survival; Prognostic risk signature

DOI: https://doi.org/10.1002/2211-5463.13288