bims-meluca 2023-06-25 papers

Aging (Albany NY). 2023 Jun 15. 15

Dissecting the alternation landscape of mitochondrial metabolism-related genes in lung adenocarcinoma and their latent mechanisms.

Xing Jin, Di Liu, Demiao Kong, Xiaojiang Zhou, Liken Zheng, Chuan Xu.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer with high incidence and unsatisfactory prognosis. The majority of LUAD patients eventually succumb to local and/or distinct metastatic recurrence. Genomic research of LUAD has broadened our understanding of this disease's biology and improved target therapies. However, the alternation landscape and characteristics of mitochondrial metabolism-related genes (MMRGs) in LUAD progression remain poorly understood. We performed a comprehensive analysis to identify the function and mechanism of MMRGs in LUAD based on the TCGA and GEO databases, which might offer therapeutic values for clinical researchers. Then, we figured out three hub prognosis-associated MMRGs (also termed as PMMRGs: ACOT11, ALDH2, and TXNRD1) that were engaged in the evolution of LUAD. To investigate the correlation between clinicopathological characteristics and MMRGs, we divided LUAD samples into two clusters (C1 and C2) based on key MMRGs. In addition, important pathways and the immune infiltration landscape affected by LUAD clusters were also delineated. Further, we nominated potential regulatory mechanisms underlying the MMRGs in LUAD development and progression. In conclusion, our integrative analysis enables a more comprehensive understanding of the mutation landscape of MMRGs in LUAD and provides an opportunity for more precise treatment.

Keywords: NSCLC; lung adenocarcinoma; mechanism; mitochondrial metabolism-related genes; prognosis

DOI: https://doi.org/10.18632/aging.204803

Nat Commun. 2023 Jun 21. 14(1): 3673

SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.

Yuelong Yan, Hongqi Teng, Qinglei Hang, Lavanya Kondiparthi, Guang Lei, Amber Horbath, Xiaoguang Liu, Chao Mao, Shiqi Wu, Li Zhuang, M James You, Masha V Poyurovsky, Li Ma, Kellen Olszewski, Boyi Gan.

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.

DOI: https://doi.org/10.1038/s41467-023-39401-9

BMC Cancer. 2023 Jun 20. 23(1): 569

E-cadherin expression in the tumor microenvironment of advanced epidermal growth factor receptor-mutant lung adenocarcinoma and the association with prognosis.

Yu-Ping Chang, Gong-Kai Huang, Yung-Che Chen, Kuo-Tung Huang, Yu-Mu Chen, Chiung-Yu Lin, Chao-Cheng Huang, Meng-Chih Lin, Chin-Chou Wang.

BACKGROUND: The expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), E-cadherin, and vimentin in lung cancer tumor microenvironment is known to impact patient survival or response to therapy. The expression of these biomarkers may also differ between primary lung tumors and brain metastatic tumors. In this study, we investigated the interaction between these biomarkers in lung tumors with or without concomitant brain metastasis and the interaction with paired brain metastatic tumors.
METHODS: The study included 48 patients with stage IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. Sixteen of the forty-eight patients were diagnosed with brain metastasis, while the remaining thirty-two were not. All sixteen patients with brain metastasis had brain tumors. The expression of PD-L1, TILs (CD8+ T lymphocytes and FOXP3+ regulatory T lymphocytes), E-cadherin, and vimentin were evaluated using immunohistochemical (IHC) staining.
RESULTS: Patients with brain metastasis exhibited a higher frequency of exon 19 deletion and uncommon EGFR mutations, a higher lung tumor vimentin score, worse progression-free survival (PFS), and overall survival (OS) than patients without brain metastasis. IHC staining showed no difference between paired lung and brain tumors. Patients with low PD-L1 expression had better PFS and OS. After multivariate analysis, higher body mass index, the presence of brain metastasis, bone metastasis, and uncommon EGFR mutations were correlated with worse PFS, while the presence of brain metastasis and high lung tumor E-cadherin score was associated with worse OS.
CONCLUSIONS: In patients with stage IV EGFR-mutant lung adenocarcinoma, high E-cadherin expression in the lung tumor might be associated with worse OS. Vimentin expression in the lung tumor was positively related to the risk of brain metastasis.

Keywords: Adenocarcinoma; E-cadherin; Epidermal growth factor receptor (EGFR); Lung cancer; Programmed death-ligand 1 (PD-L1); Tumor-infiltrating lymphocytes; Vimentin

DOI: https://doi.org/10.1186/s12885-023-10980-6

Front Immunol. 2023 ;14 1070953

Development and validation of polyamines metabolism-associated gene signatures to predict prognosis and immunotherapy response in lung adenocarcinoma.

Ning Wang, Mengyu Chai, Lingye Zhu, Jingjing Liu, Chang Yu, Xiaoying Huang.

Background: Polyamines metabolism is closely related to tumor development and progression, as well as tumor microenvironment (TME). In this study, we focused on exploring whether polyamines metabolism-associated genes would provide prognosis and immunotherapy response prediction in lung adenocarcinoma (LUAD).
Methods: The expression profile data of polyamines metabolism-associated genes were acquired from the Cancer Genome Atlas (TCGA) database. Utilizing the least absolute shrinkage and selection operator (LASSO) algorithm, we created a risk score model according to polyamines metabolism-associated gene signatures. Meanwhile, an independent cohort (GSE72094) was employed to validate this model. Through the univariate and multivariate Cox regression analyses, the independent prognostic factors were identified. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect their expression in LUAD cells. By consensus clustering analysis, polyamines metabolism-associated subgroups were determined in LUAD patients, with differential gene expression, prognosis, and immune characteristics analyses explored.
Results: A total of 59 polyamines metabolism genes were collected for this study, of which 14 genes were identified for the construction of risk score model using LASSO method. High- and low- risk groups of LUAD patients in TCGA cohort were distinguished via this model, and high-risk group presented dismal clinical outcomes. The same prognostic prediction of this model had been also validated in GSE72094 cohort. Meanwhile, three independent prognostic factors (PSMC6, SMOX, SMS) were determined for constructing the nomogram, and they were all upregulated in LUAD cells. In addition, two distinct subgroups (C1 and C2) were identified in LUAD patients. Comparing the two subgroups, 291 differentially expressed genes (DEGs) were acquired, mainly enriching in organelle fission, nuclear division, and cell cycle. Comparing to C1 subgroup, the patients in C2 subgroup had favorable clinical outcomes, increased immune cells infiltration, and effective immunotherapy response.
Conclusion: This study identified polyamines metabolism-associated gene signatures for predicting the patients' survival, and they were also linked to immune cells infiltration and immunotherapy response in LUAD patients.

Keywords: immunotherapy response; lung adenocarcinoma; polyamines metabolism; prognosis; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2023.1070953