bims-meluca 2021-08-22 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–08–22
six 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

Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1.
A Novel Integrated Metabolism-Immunity Gene Expression Model Predicts the Prognosis of Lung Adenocarcinoma Patients.
Lower prognostic nutritional index is associated with poorer survival in patients receiving ımmune-checkpoint ınhibitors.
Effect of Menadione and Combination of Gemcitabine and Cisplatin on Cancer Stem Cells in Human Non-small Cell Lung Cancer (NSCLC) Cell Line A549.
Fibroblast growth factor 11 (FGF11) promotes non-small cell lung cancer (NSCLC) progression by regulating hypoxia signaling pathway.
Omega-3 Fatty Acids Supplementation Improve Nutritional Status and Inflammatory Response in Patients With Lung Cancer: A Randomized Clinical Trial.

Nat Cancer. 2020 Jun;1(6): 589-602

Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1.

Rodrigo Romero, Francisco J Sánchez-Rivera, Peter M K Westcott, Kim L Mercer, Arjun Bhutkar, Alexander Muir, Tania J González-Robles, Swanny A Lamboy-Rodríguez, Laura Z Liao, Sheng Rong Ng, Leanne Li, Caterina I Colón, Santiago Naranjo, Mary Clare Beytagh, Caroline A Lewis, Peggy P Hsu, Roderick T Bronson, Matthew G Vander Heiden, Tyler Jacks.

Approximately 20-30% of human lung adenocarcinomas (LUAD) harbor loss-of-function (LOF) mutations in Kelch-like ECH Associated-Protein 1 (KEAP1), which lead to hyperactivation of the nuclear factor, erythroid 2-like 2 (NRF2) antioxidant pathway and correlate with poor prognosis1-3. We previously showed that Keap1 mutation accelerates KRAS-driven LUAD and produces a marked dependency on glutaminolysis4. To extend the investigation of genetic dependencies in the context of Keap1 mutation, we performed a druggable genome CRISPR-Cas9 screen in Keap1-mutant cells. This analysis uncovered a profound Keap1 mutant-specific dependency on solute carrier family 33 member 1 (Slc33a1), an endomembrane-associated protein with roles in autophagy regulation5, as well as a series of functionally-related genes implicated in the unfolded protein response. Targeted genetic and biochemical experiments using mouse and human Keap1-mutant tumor lines, as well as preclinical genetically-engineered mouse models (GEMMs) of LUAD, validate Slc33a1 as a robust Keap1-mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to Slc33a1 dependency. Overall, our study provides a strong rationale for stratification of patients harboring KEAP1-mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with GEMMs to identify and validate genotype-specific therapeutic targets.

DOI: https://doi.org/10.1038/s43018-020-0071-1
Front Pharmacol. 2021 ;12 728368

A Novel Integrated Metabolism-Immunity Gene Expression Model Predicts the Prognosis of Lung Adenocarcinoma Patients.

Songming Chen, Yumei Duan, Yanhao Wu, Desong Yang, Jian An.

  Background: Although multiple metabolic pathways are involved in the initiation, progression, and therapy of lung adenocarcinoma (LUAD), the tumor microenvironment (TME) for immune cell infiltration that is regulated by metabolic enzymes has not yet been characterized. Methods: 517 LUAD samples and 59 non-tumor samples were obtained from The Cancer Genome Atlas (TCGA) database as the training cohort. Kaplan-Meier analysis and Univariate Cox analysis were applied to screen the candidate metabolic enzymes for their role in relation to survival rate in LUAD patients. A prognostic metabolic enzyme signature, termed the metabolic gene risk score (MGRS), was established based on multivariate Cox proportional hazards regression analysis and was verified in an independent test cohort, GSE31210. In addition, we analyzed the immune cell infiltration characteristics in patients grouped by their Risk Score. Furthermore, the prognostic value of these four enzymes was verified in another independent cohort by immunohistochemistry and an optimized model of the metabolic-immune protein risk score (MIPRS) was constructed. Results: The MGRS model comprising 4 genes (TYMS, NME4, LDHA, and SMOX) was developed to classify patients into high-risk and low-risk groups. Patients with a high-risk score had a poor prognosis and exhibited activated carbon and nucleotide metabolism, both of which were associated with changes to TME immune cell infiltration characteristics. In addition, the optimized MIPRS model showed more accurate predictive power in prognosis of LUAD. Conclusion: Our study revealed an integrated metabolic enzyme signature as a reliable prognostic tool to accurately predict the prognosis of LUAD.

Keywords:  CD19; CD68; LDHA; NME4; SMOX; TYMS; lung adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2021.728368
Biomark Med. 2021 Aug 16.

Lower prognostic nutritional index is associated with poorer survival in patients receiving ımmune-checkpoint ınhibitors.

Deniz C Guven, Oktay H Aktepe, Hakan Taban, Burak Y Aktas, Gurkan Guner, Hasan C Yildirim, Taha K Sahin, Melek S Aksun, Omer Dizdar, Sercan Aksoy, Mustafa Erman, Suayib Yalcin, Saadettin Kilickap.

  Aim: Blood-based biomarkers like prognostic nutritional index (PNI) are readily available biomarkers for immunotherapy efficacy, although the data are limited. So, we aimed to evaluate the association between PNI and overall survival (OS) in immunotherapy-treated patients. Materials & methods: For this retrospective cohort study, data of 150 immunotherapy-treated advanced cancer patients were evaluated. The association between clinical factors and OS was evaluated with multivariate Cox-regression analyses. Results: After a median follow-up of 8.5 months, 94 patients died. The median OS was 11.07 months. The low PNI (hazard ratio [HR]: 2.065; p = 0.001), high lactate dehydrogenase (HR: 2.515; p = 0.001) and poor Eastern Cooperative Oncology Group (ECOG) status (HR: 2.164; p = 0.009) was associated with poorer OS in multivariate analyses. Conclusion: In our experience, survival with immunotherapy was impaired in patients with lower PNI and higher lactate dehydrogenase levels and poorer ECOG status.

Keywords:  ECOG; LDH; biomarkers; immunotherapy; prognostic nutritional index

DOI:  https://doi.org/10.2217/bmm-2020-0674
Iran J Pharm Res. 2021 ;20(1): 105-117

Effect of Menadione and Combination of Gemcitabine and Cisplatin on Cancer Stem Cells in Human Non-small Cell Lung Cancer (NSCLC) Cell Line A549.

Sara Soltanian, Mahboubeh Sheikhbahaei.

  Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Chemotherapy-induced adverse effects and resistance of NSCLC to conventional drugs reduce the efficacy of current therapies. Tumors contain a small population of cancer stem cells (CSCs) that play a critical role in tumor initiation, maintenance, and drug resistance that finally lead to cancer recurrence. Therefore, CSC-targeting therapies can offer the best hope for developing curative cancer therapies. Vitamins have a high potential for cancer prevention and treatment. Vitamins also ameliorate the side effects which occur in chemo-radio therapy. Menadione (2-methyl-1,4-naphthoquinone/vitamin-K3) is a synthetic form of vitamin K that indicated antitumor activities. The purpose of this study was to evaluate the anti-CSCs effect of menadione and combination of cisplatin and gemcitabine as a first-line treatment in patients with NSCLC on the NSCLC cell line A549. MTT results displayed decreased cell survival after treatment with cisplatin/gemcitabine for 48 h treatment (IC50 values 0.25 µM for cisplatin and 5 µM for gemcitabine). Menadione also inhibited the cell growth in A549 cells (IC50: 16 µM). Quantitative RT-PCR showed significant downregulation of CSC markers (Oct4, Nanog, Sox2, Aldh1, Abcb1, CD44, and CD133) and Snail, epithelial-mesenchymal transition marker, after treatment with menadione and cisplatin/gemcitabine. Flow cytometry showed CD44-positive cells that constitute a high percentage (70%) of A549 cells reduced significantly after treatment with cisplatin/gemcitabine or menadione. However, A549 cells did not show a significant population positive for CD133 and ABCB1 (less than 0.05%), and these fractions did not change after treatment with two agents.

Keywords:  Cancer stem cell markers; Cancer stem cells; Cisplatin; Gemcitabine; Menadione; Non-small cell lung cancer

DOI:  https://doi.org/10.22037/ijpr.2020.112373.13715
J Transl Med. 2021 Aug 17. 19(1): 353

Fibroblast growth factor 11 (FGF11) promotes non-small cell lung cancer (NSCLC) progression by regulating hypoxia signaling pathway.

Xiaowei Wu, Minjie Li, Ying Li, Yu Deng, Shun Ke, Fan Li, Yujin Wang, Shuchang Zhou.

   BACKGROUND: Accumulating evidence highlights the critical roles of fibroblast growth factors (FGFs) in regulating the progression of multiple human cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the role of FGF11 in the progression of NSCLC.
METHODS: Previously published transcriptomic data (GSE75037 and GSE81089) were used to compare FGF11 expression level between NSCLC tumor tissues and adjacent normal tissues. 100 cases of NSCLC tumor tissues and 30 cases of matched adjacent normal tissues were used to validate FGF11 expression at mRNA and protein level by qPCR and immunohistochemistry. Bioinformatics analysis and dual luciferase reporter analysis were performed to confirm the regulatory effect of miR-525-5p on FGF11 expression. CCK-8 assay and transwell migration assay were employed to examine cellular proliferation, migration and invasion. Gene set enrichment analysis (GSEA) was performed to identify the signaling pathway associated with FGF11 expression. Finally, the functional role of FGF11 in NSCLC tumor growth was evaluated by in vivo study.
RESULTS: FGF11 was upregulated in NSCLC tumor tissues and tumor cell lines. High FGF11 expression was associated with a poor prognosis in NSCLC patients. In vitro loss- and gain-of function experiments demonstrated that FGF11 knockdown inhibited, whereas FGF11 overexpression promoted the proliferation, migration and invasion of NSCLC cells. Dual luciferase reporter assay confirmed that FGF11 was downregulated by miR-525-5p, and the effect of FGF11 on cell proliferation, migration and invasion could be interfered by miR-525-5p. GSEA analysis further revealed that FGF11 expression was enriched with genes in hypoxia signaling pathway and the oncogenic function of FGF11 could be suppressed by knocking down HIF-1α in NSCLC cells. Moreover, FGF11 knockdown suppressed NSCLC tumor growth whereas FGF11 overexpression promoted tumor growth in vivo.
CONCLUSIONS: Our study showed that FGF11 functions as an oncogene in tumor NSCLC progression. miR-525-5p seems to negatively regulate FGF11 and the oncogenic role of FGF11 is dependent on the upregulation of HIF-1α. Our study suggests that targeting FGF11 and HIF-1α may serve as novel strategies for the treatment of NSCLC.

Keywords:  Cell proliferation; FGF11; HIF-1α; Hypoxia; NSCLC

DOI:  https://doi.org/10.1186/s12967-021-03018-7
Front Nutr. 2021 ;8 686752

Omega-3 Fatty Acids Supplementation Improve Nutritional Status and Inflammatory Response in Patients With Lung Cancer: A Randomized Clinical Trial.

Mingjin Cheng, Shengqiang Zhang, Chengdong Ning, Qianlun Huo.

  Background and Aims: Clinical studies have reported positive results with omega-3 supplements in patients with cancer. This study aimed to evaluate the efficacy of omega-3 fatty acid supplementation in improving the nutritional status and inflammatory markers of patients with lung cancer. Methods: In a randomized, double-blind, parallel design trial, 60 patients with lung cancer at nutritional status/risk based on the Nutrition Risk Screening 2002 were randomized to be allocated to two study groups, receiving omega-3 fatty acid supplements [eicosapentaenoic acid (EPA) 1.6 g and docosahexaenoic acid (DHA) 0.8 g] or placebo for 12 weeks. Anthropometric measurements [weight, body mass index (BMI), the circumference of the upper arm, and skinfold thickness of triceps], nutrition-based laboratory indices (hemoglobin, albumin, triglyceride, and cholesterol), and inflammatory markers [C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6)] were measured before and after the intervention as study outcomes. Results: No significant difference between the two study groups was observed regarding basic characteristics and study outcomes. Compared with placebo group, omega-3 fatty acid supplementation group showed significant higher weight (66.71 ± 9.17 vs. 61.33 ± 8.03, p = 0.021), albumin (4.74 ± 0.80 vs. 4.21 ± 0.77, p = 0.013), and triglyceride (130.90 ± 25.17 vs. 119.07 ± 14.44, p = 0.032). Inflammatory markers were significantly reduced in omega-3 group compared to placebo (CRP 1.42 ± 0.63 vs. 3.00 ± 1.05, p = 0.001 and TNF-α 1.92 ± 0.65 vs. 4.24 ± 1.19, p = 0.001). No significant difference was observed between the two study groups regarding changes in BMI, the circumference of the upper arm, skinfold thickness of triceps, triglyceride, cholesterol, and IL-6 (p > 0.05). Conclusions: Omega-3 fatty acid supplementation can improve nutritional status and suppress the systemic inflammatory response in patients with lung cancer. Clinical Trial Registration:www.socialscienceregistry.org, identifier: AEARCTR-0007165.

Keywords:  inflammation; lung cancer; nutrition; omega-3 fatty acids; supplement

DOI:  https://doi.org/10.3389/fnut.2021.686752