bims-meluca 2022-12-04 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–12–04
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Stearoyl-CoA Desaturase-1 dependent lipid droplets accumulation in cancer-associated fibroblasts facilitates the progression of lung cancer.
A Subset of VEGFR-TKIs Activates AMPK in LKB1-mutant Lung Cancer.
Identification of eIF6 as a prognostic factor that drives tumor progression and predicts arsenic trioxide efficacy in lung adenocarcinoma.
Comprehensive analyses of one-carbon metabolism related genes and their association with prognosis, tumor microenvironment, chemotherapy resistance and immunotherapy in lung adenocarcinoma.
Alterations in the omics profiles in mevalonate pathway-inhibited cancer cells.
Characterizing microbiota and metabolomics analysis to identify candidate biomarkers in lung cancer.
Guidelines on lung adenocarcinoma prognosis based on immuno-glycolysis-related genes.
Macrophage-specific xCT deficiency drives immune activation and boosts responses to immune checkpoint blockade in lung cancer.
Fructose utilization enhanced by GLUT5 promotes lung cancer cell migration via activating glycolysis/AKT pathway.

Int J Biol Sci. 2022 ;18(16): 6114-6128

Stearoyl-CoA Desaturase-1 dependent lipid droplets accumulation in cancer-associated fibroblasts facilitates the progression of lung cancer.

Yana Zhang, Zhuoyu Gu, Jiajia Wan, Xiaohan Lou, Shuangqing Liu, Yuan Wang, Yangyang Bian, Fei Wang, Zhenzhen Li, Zhihai Qin.

  Rationale: Cancer-associated fibroblasts (CAFs) are the main components in the tumor microenvironment (TME) and facilitate lung cancer progression. Studies have reported that metabolic reprogramming can regulate the function of CAFs, especially abnormal lipid metabolism. Lipid droplets (LDs) are ubiquitous organelles that store neutral lipids and have a crucial role in lipid metabolism. However, little is known about the synthesis and functions of LDs in lung CAFs. Methods: TetO-EGFRL858R; CCSP-rtTA transgenic mouse model was used to establish a spontaneous pulmonary tumor model and investigate the accumulation of LDs in CAFs. The effect of LDs accumulation on the phenotype change of fibroblasts was estimated in vitro using mouse fibroblast cell lines. RNA sequencing, Western blotting, RT-PCR, and DNA-pull down were performed to determine the mechanism of LDs synthesis in fibroblasts. Results: We found that LDs were enriched in lung CAFs and induced the pro-tumoral phenotype of CAFs with increased expression of α-smooth muscle actin (α-SMA) and Collagen alpha-2 (I) chain (COL1A2). As the main regulator, hypoxia-inducible factor-1α (HIF-1α) was highly expressed in activated fibroblasts and increased the content of LDs. RNA-sequencing results showed that Stearoyl-CoA Desaturase1 (SCD1) was a downstream gene of HIF-1α, which upregulated the number of LDs in fibroblasts. Importantly, SCD1 inhibition reduced the growth of lung tumors, which was correlated with LDs decrease in CAFs. Analysis of human lung adenocarcinoma tissue chip revealed that CAFs with a high level of SCD1 were positively correlated with the expression of HIF-1α and poor survival in lung cancer patients. Conclusions: The HIF-1α/SCD1 axis regulates the accumulation of LDs in CAFs, which might represent a novel target for lung cancer therapy.

Keywords:  Cancer-associated Fibroblasts; Hypoxia-Inducible Factor-1α; Lipid Droplets; Lung Cancer; SCD1

DOI:  https://doi.org/10.7150/ijbs.74924
Cancer Sci. 2022 Dec 02.

A Subset of VEGFR-TKIs Activates AMPK in LKB1-mutant Lung Cancer.

Lujie Yang, Qin Zhang, Yanli Xiong, Zhaoqian Dang, He Xiao, Qian Chen, Xiaoyan Dai, Lei Zhang, Jianwu Zhu, Dong Wang, Mengxia Li.

  The mutation of tumor suppressor gene liver kinase B1 (LKB1) has a prevalence of about 20% in non-small cell lung cancer (NSCLC). LKB1-mutant lung cancer is characterized by enhanced aggressiveness and immune escape, and is associated with poor prognosis. Therefore, it is urgent to develop effective therapeutic methods for LKB1-mutant NSCLC. Recently, apatinib, a VEGFR-TKI, was found to significantly improve the outcome of LKB1-mutant NSCLC, but the mechanism is not completely clear. In this study, AMP-activated protein kinase (AMPK), the crucial down-stream kinase of LKB1 was excavated as the potential target of apatinib. Biochemical experiments verified that apatinib is a direct AMPK activator. Moreover, clinically available VEGFR-TKIs were found to regulate AMPK differently that, apatinib and anlotinib can directly activate AMPK, while axitinib and sunitinib can directly inhibit AMPK. Activation of AMPK by apatinib leads to the phosphorylation of acetyl-CoA carboxylase (ACC) and inhibition of de novo fatty acid synthesis (FAsyn), which is up-regulated in LKB1-null cancers. Moreover, the killing effect of apatinib was obviously enhanced under delipidated condition, and the combination of exogenous FA restriction with apatinib treatment can be a promising method for treating LKB1-mutant NSCLC. This study discovered AMPK as an important off-target of apatinib, and elucidated different effects of this cluster of VEGFR-TKIs on AMPK. This finding can be the basis for the accurate and combined application of these drugs in clinic, and highlights the subset of VEGFR-TKIs including apatinib and anlotinib are potentially valuable in the treatment of LKB1-mutant NSCLC.

Keywords:  AMPK; Lung cancer; STK11; VEGFR-TKI; fatty acid metabolism

DOI:  https://doi.org/10.1111/cas.15677
Mol Biol Rep. 2022 Nov 26.

Identification of eIF6 as a prognostic factor that drives tumor progression and predicts arsenic trioxide efficacy in lung adenocarcinoma.

Yan Shen, Ruihong Zhang, Xiangrui Li.

   BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide. Dysregulation of mRNA translation can contribute to the development and progression of cancer whilst also having an impact on the prognosis of different types of malignancies. Eukaryotic translation initiation factors (eIFs) have been reported to serve a key role in the initiation of mRNA translation. However, little was known about the association between eIF6 and lung adenocarcinoma (LUAD) progression. We aimed to elucidate the roles of eIF6 in LUAD tumorigenesis.
METHODS: Bioinformatic analysis was conducted to assess the clinical significance of eIF6 in LUAD. CCK-8, colony formation assays were used to evaluate the biological roles of eIF6. The subcutaneous model was used to assess the in vivo roles of eIF6.
RESULTS: In the present study, it was found that eIF6 expression was significantly higher in LUAD samples compared with that in normal lung tissues. Higher expression levels of eIF6 were found to be associated with more advanced clinical stages of LUAD and poorer prognoses in patients with LUAD. Subsequently, overexpression of eIF6 was demonstrated to promote LUAD cell proliferation, migration and invasion, which are features of metastasis, in vitro. By contrast, inhibition of eIF6 induced cell cycle arrest and apoptosis in LUAD cells. Further bioinformatics analysis and experimental assays revealed that eIF6 expression positively correlated with the mRNA expression of stemness-associated genes in LUAD cells. Targeting eIF6 suppressed the sphere formation capacity of LUAD cells. In addition, data from the subcutaneous xenograft model in vivo also suggested that eIF6 deficiency could significantly delay tumor growth and improve the prognosis of mice. Targeting eIF6 rendered LUAD cells sensitive to arsenic trioxide treatment.
CONCLUSION: The present study suggest that eIF6 can serve as a prognostic biomarker and a potential therapeutic target for patients with LUAD.

Keywords:  Arsenic trioxide; Eukaryotic translation initiation factor 6; Lung adenocarcinoma; Proliferation; Stemness

DOI:  https://doi.org/10.1007/s11033-022-07917-w
Front Mol Biosci. 2022 ;9 1034208

Comprehensive analyses of one-carbon metabolism related genes and their association with prognosis, tumor microenvironment, chemotherapy resistance and immunotherapy in lung adenocarcinoma.

Ning Zhou, Quanying Tang, Haochuan Yu, Tong Li, Fan Ren, Lingling Zu, Gang Chen, Jun Chen, Song Xu.

  Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and is a global public health concern. One-carbon (1C) metabolism plays a crucial role in the occurrence and development of multiple cancer types. However, there are limited studies investigating 1C metabolism in LUAD. This study aims to evaluate the prognostic value of 1C metabolism-related genes in LUAD and to explore the potential correlation of these genes with gene methylation, the tumor microenvironment, and immunotherapy. Methods: We identified 26 1C metabolism-related genes and performed a Kaplan-Meier and Cox regression analysis to evaluate the prognostic value of these genes. Consensus clustering was further performed to determine the 1C metabolism-related gene patterns in LUAD. The clinical and molecular characteristics of subgroups were investigated based on consensus clustering. CIBERSORT and ssGSEA algorithms were used to calculate the relative infiltration levels of multiple immune cell subsets. The relationship between 1C metabolism-related genes and drug sensitivity to immunotherapy was evaluated using the CellMiner database and IMvigor210 cohort, respectively. Results: The expression levels of 23 1C metabolism-related genes were significantly different between LUAD tumor tissues and normal tissues. Seventeen of these genes were related to prognosis. Two clusters (cluster 1 and cluster 2) were identified among 497 LUAD samples based on the expression of 7 prognosis-related genes. Distinct expression patterns were observed between the two clusters. Compared to cluster 2, cluster 1 was characterized by inferior overall survival (OS) (median OS = 41 vs. 60 months, p = 0.00031), increased tumor mutation burden (15.8 vs. 7.5 mut/Mb, p < 0.001), high expression of PD-1 (p < 0.001) and PD-L1 (p < 0.001), as well as enhanced immune infiltration. 1C metabolism-related genes were positively correlated with the expression of methylation enzymes, and a lower methylation level was observed in cluster 1 (p = 0.0062). Patients in cluster 1 were resistant to chemotherapy drugs including pemetrexed, gemcitabine, paclitaxel, etoposide, oxaliplatin, and carboplatin. The specific expression pattern of 1C metabolism-related genes was correlated with a better OS in patients treated with immunotherapy (median OS: 11.2 vs. 7.8 months, p = 0.0034). Conclusion: This study highlights that 1C metabolism is correlated with the prognosis of LUAD patients and immunotherapy efficacy. Our findings provide novel insights into the role of 1C metabolism in the occurrence, development, and treatment of LUAD, and can assist in guiding immunotherapy for LUAD patients.

Keywords:  chemotherapy resistance; immune cell infiltrate; immunotherapy; lung adenocarcinoma; one-carbon metabolism

DOI:  https://doi.org/10.3389/fmolb.2022.1034208
Life Sci. 2022 Nov 28. pii: S0024-3205(22)00949-3. [Epub ahead of print] 121249

Alterations in the omics profiles in mevalonate pathway-inhibited cancer cells.

Tomoko Warita, Nanami Irie, Yaxuan Zhou, Jiro Tashiro, Akihiro Sugiura, Zoltán N Oltvai, Katsuhiko Warita.

   AIMS: Statins, cholesterol-lowering drugs, are potential therapeutic agents for inhibiting cancer proliferation. However, the mechanisms that mediate the effects of statins, the homeostatic responses of tumor cells to statin therapy, and the modes underlying the antitumor effects of statins remain unclear.
MAIN METHODS: To uncover the effects of statins on cancer cells in vitro, we performed transcriptome and metabolome analyses on atorvastatin-treated statin-resistant and statin-sensitive lung cancer cells.
KEY FINDINGS: The results of Gene Ontology terms and pathway enrichment analyses showed that after 24 h of atorvastatin treatment, the expression of cell cycle- and DNA replication-related genes was significantly decreased in the statin-sensitive cancer cells. The results of metabolome analysis showed that the components of polyamine metabolism and purine metabolism, glycolysis, and pentose phosphate pathway were decreased in the statin-sensitive cancer cells.
SIGNIFICANCE: Differences in cellular properties between statin-sensitive and statin-resistant cancer cells revealed additional candidates for therapeutic targets in statin-treated cancer cells and suggested that inhibiting these metabolic pathways could improve efficacy. In conclusion, combining statins with inhibitors of polyamine metabolism (cell proliferation and protein translation), purine metabolism (DNA synthesis), glycolytic system (energy production), and pentose phosphate pathway (antioxidant stress) might enhance the anticancer effects of statins.

Keywords:  Cancer cells; Glycolysis; Metabolome; Polyamine metabolism; Statins; Transcriptome

DOI:  https://doi.org/10.1016/j.lfs.2022.121249
Front Oncol. 2022 ;12 1058436

Characterizing microbiota and metabolomics analysis to identify candidate biomarkers in lung cancer.

Bo Liu, Yige Li, Lijun Suo, Wei Zhang, Hongyun Cao, Ruicai Wang, Jiahui Luan, Xiaofeng Yu, Liang Dong, Wenjing Wang, Shiyang Xu, Shiyong Lu, Mei Shi.

   Background: Lung cancer is the leading malignant disease and cause of cancer-related death worldwide. Most patients with lung cancer had insignificant early symptoms so that most of them were diagnosed at an advanced stage. In addition to factors such as smoking, pollution, lung microbiome and its metabolites play vital roles in the development of lung cancer. However, the interaction between lung microbiota and carcinogenesis is lack of systematically characterized and controversial. Therefore, the purpose of this study was to excavate the features of the lung microbiota and metabolites in patients and verify potential biomarkers for lung cancer diagnosis.
Methods: Lung tissue flushing solutions and bronchoalveolar lavage fluid samples came from patients with lung cancer and non-lung cancer. The composition and variations of the microbiota and metabolites in samples were explored using muti-omics technologies including 16S rRNA amplicon sequencing, metagenomics and metabolomics.
Results: The metabolomics analysis indicated that 40 different metabolites, such as 9,10-DHOME, sphingosine, and cysteinyl-valine, were statistically significant between two groups (VIP > 1 and P < 0.05). These metabolites were significantly enriched into 11 signal pathways including sphingolipid, autophagy and apoptosis signaling pathway (P < 0.05). The analysis of lung microbiota showed that significant changes reflected the decrease of microbial diversity, changes of distribution of microbial taxa, and variability of the correlation networks of lung microbiota in lung cancer patients. In particular, we found that oral commensal microbiota and multiple probiotics might be connected with the occurrence and progression of lung cancer. Moreover, our study found 3 metabolites and 9 species with significantly differences, which might be regarded as the potential clinical diagnostic markers associated with lung cancer.
Conclusions: Lung microbiota and metabolites might play important roles in the pathogenesis of lung cancer, and the altered metabolites and microbiota might have the potential to be clinical diagnostic markers and therapeutic targets associated with lung cancer.

Keywords:  16S rRNA amplicon sequencing; biomarker; lung cancer; lung microbiota; metabolomics

DOI:  https://doi.org/10.3389/fonc.2022.1058436
Clin Transl Oncol. 2022 Nov 29.

Guidelines on lung adenocarcinoma prognosis based on immuno-glycolysis-related genes.

Yuting Zhang, Wen Qin, Wenhui Zhang, Yi Qin, You Lang Zhou.

   OBJECTIVES: This study developed a new model for risk assessment of immuno-glycolysis-related genes for lung adenocarcinoma (LUAD) patients to predict prognosis and immunotherapy efficacy.
METHODS: LUAD samples and data obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases are used as training and test columns, respectively. Twenty-two (22) immuno-glycolysis-related genes were screened, the patients diagnosed with LUAD were divided into two molecular subtypes by consensus clustering of these genes. The initial prognosis model was developed using the multiple regression analysis method and Receiver Operating characteristic (ROC) analysis was used to verify its predictive potential. Gene set enrichment analysis (GSEA) showed the immune activities and pathways in different risk populations, we calculated immune checkpoints, immune escape, immune phenomena (IPS), and tumor mutation burden (TMB) based on TCGA datasets. Finally, the relationship between the model and drug sensitivity was analyzed.
RESULTS: Fifteen (15) key differentially expressed genes (DEGs) with prognostic value were screened and a new prognostic model was constructed. Four hundred and forty-three (443) samples were grouped into two different risk cohorts based on median model risk values. It was observed that survival rates in high-risk groups were significantly low. ROC curves were used to evaluate the model's accuracy in determining the survival time and clinical outcome of LUAD patients. Cox analysis of various clinical factors proved that the risk score has great potential as an independent prognostic factor. The results of immunological analysis can reveal the immune infiltration and the activity of related functions in different pathways in the two risk groups, and immunotherapy was more effective in low-risk patients. Most chemotherapeutic agents are more sensitive to low-risk patients, making them more likely to benefit.
CONCLUSION: A novel prognostic model for LUAD patients was established based on IGRG, which could more accurately predict the prognosis and an effective immunotherapy approach for patients.

Keywords:  Bioinformatics; Glycolysis; Immune; Lung adenocarcinoma; Prognosis

DOI:  https://doi.org/10.1007/s12094-022-03000-9
Cancer Lett. 2022 Nov 28. pii: S0304-3835(22)00508-0. [Epub ahead of print] 216021

Macrophage-specific xCT deficiency drives immune activation and boosts responses to immune checkpoint blockade in lung cancer.

Bufu Tang, Yajie Wang, Wangting Xu, Jinyu Zhu, Qiaoyou Weng, Weiqian Chen, Shiji Fang, Yang Yang, Rongfang Qiu, Minjiang Chen, Weiyang Mao, Min Xu, Zhongwei Zhao, Songhua Cai, Hongbing Zhang, Jiansong Ji.

  Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor microenvironment (TME), which promotes tumor growth, immunosuppression and angiogenesis. Because of the high plasticity of macrophages and the extremely complex tumor microenvironment, the mechanism of TAMs in cancer progression is still largely unknown. In this study, we found that xCT (SLC7A11) was overexpressed in lung cancer-associated macrophages. Higher xCT in TAMs was associated with poor prognosis and was an independent predictive factor in lung cancer. In addition, lung cancer growth and progression was inhibited in xCT knockout mice, especially macrophage-specific xCT knockout mice. We also found that the deletion of macrophage xCT inhibited AKT/STAT6 signaling activation and reduced M2-type polarization of TAMs. Macrophage xCT deletion recruited more CD8+ T cells and activated the lung cancer cell-mediated and IFN-γ-induced JAK/STAT1 axis and increased the expression of its target genes, including CXCL10 and CD274. The combination of macrophage xCT deletion and anti-PDL1 antibody achieved better tumor inhibition. Finally, combining the xCT inhibitor erastin with an anti-PDL1 antibody was more potent in inhibiting lung cancer progression. Therefore, suppression of xCT may overcome resistance to cancer immunotherapy.

Keywords:  Anti-tumor immunity; PDL-1; STATs; System xc(−); TAMs

DOI:  https://doi.org/10.1016/j.canlet.2022.216021
Clin Transl Oncol. 2022 Dec 01.

Fructose utilization enhanced by GLUT5 promotes lung cancer cell migration via activating glycolysis/AKT pathway.

Jing Yang, Changsheng Dong, Jia Wu, Dan Liu, Qin Luo, Xing Jin.

   PURPOSE: Lung cancer is the leading cause of cancer-related mortalities worldwide, and metastasis contributes to a large number of deaths in lung carcinoma patients. New approaches for anti-metastatic treatment are urgently needed. Enhanced fructose metabolism mediated by GLUT5 directly contributes to cancer metastasis. However, the underlying mechanism remains to be elucidated, which we aimed to explore in this study.
METHODS: The overexpression and knockdown of SLC2A5, the encoding gene of GLUT5, were established by retrovirus system and CRISPR/Cas9 technology, respectively. Cell migration was conducted by trans-well assay. Western blotting assay was carried out to detect the expression of GLUT5, total AKT, phosphorylated AKT (pAKT-S473 and pAKT-T308) and LDHA. Lactate production was measured by colorimetric assay. Experimental lung metastasis model by tail vein injection was constructed to evaluate the metastatic potential of GLUT5 in vivo.
RESULTS: Overexpression of SLC2A5 promoted migration of lung cancer cells both in vitro and in vivo, and shortened the overall survival of mice. While, SLC2A5 deletion blocked the migration of lung cancer cells. GLUT5-mediated fructose utilization upregulated phosphorylated AKT, which was responsible for enhanced migration of lung cancer cells. Additionally, GLUT5-mediated fructose utilization boosted glycolysis with overproduction of lactate, resulting in upregulation of phosphorylated AKT. Moreover, lung cancer cell migration and AKT activation were restrained by glycolysis inhibitor 2-deoxy-D-glucose (2-DG) or GLUT5-specific inhibitor 2,5-anhydro-D-mannitol (2,5-AM).
CONCLUSION: Our study unveils glycolysis/lactate/AKT pathway is responsible for lung cancer cell migration induced by GLUT5-mediated fructose metabolism, providing a potential therapeutic avenue for lung cancer metastasis.

Keywords:  AKT; Fructose; GLUT5; Glycolysis; Lung cancer; Migration

DOI:  https://doi.org/10.1007/s12094-022-03015-2