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Background: Single‐cell transcriptomics has been used to investigate various tumors to elucidate the molecular distinction of all cell type compositions of a complex mix. Aims: This study aimed to investigate malignant‐cell‐specific genes to explore diagnostic and therapeutic biomarkers using single‐cell transcriptomic data of lung adenocarcinoma. Materials & Methods: 10X single‐cell RNA‐seq data of fourteen patients with lung adenocarcinoma were analyzed. Genes that expressed differentially and those with higher confidence to distinguish tumor cells from normal cells were picked out using the ROC curves. The LASSO regression method was used to select most markedly correlated genes to predict the malignancy of every single cell within a model. We also conducted further experiments to determine their roles in lung cancer in vitro. Results: Twenty two thousand four hundred and ninety one tumor and 181 666 normal single cells were analyzed where 369 genes were found to be specifically expressed in single malignant cells. Seventy of them, encoding secreted or membrane‐bound proteins, showed involvement in cell‐to‐cell communications in tumor biology. KRT18 and the other six genes were identified as predictors to distinguish single malignant cells and were integrated to construct an accurate (96.1%) predicting model. Notably, IRX2, SPINK13, and CAPN8 outperformed the other four genes. Further experiments confirmed the upregulation of them in lung adenocarcinoma at both tissue and cell levels. Proliferative capacities of lung adenocarcinoma cells were attenuated by knocking‐down of either of them. However, targeting CAPN8, IRX2, or SPINK13 hardly exerted a cytotoxic effect on these cells. Discussion: Apart from the current model, similar tools were still warranted using single‐cell RNA‐seq data of more types of tumors. The three genes identified as potential therapeutic targets in the present study still need to be validated in more in lung cancer. Conclusion: Our model can aid the analyses of single‐cell sequencing data. CAPN8, IRX2, and SPINK13 may serve as novel targets of targeted and immune‐based therapies in lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer mortality and lung adenocarcinoma (LUAD) accounts for more than half of all lung cancer cases. Tumor elimination is mostly hindered by drug resistance and the mechanisms remain to be explored in LUAD. CRISPR screens in cell and murine models and single-cell RNA sequencing were conducted, which identified MAF bZIP transcription factor F (MAFF) as a critical factor regulating tumor growth and treatment resistance in LUAD. RNA and ChIP sequencing analyses were performed for transcriptional target expression and specific binding sites of MAFF. Functions of MAFF in inhibiting tumor growth and promoting cisplatin or irradiation efficacy were investigated using cellular and xenograft models. Patients with lung adenocarcinoma and reduced MAFF expression had worse clinical outcomes. MAFF inhibited tumor cell proliferation by regulating the expression of SLC7A11, CDK6, and CDKN2C, promoting ferroptosis and preventing cell cycle progression from G1 to S. MAFF also conferred tumor cells vulnerable to cisplatin-based or ionizing radiation treatments. MAFF reduction was a final event in the acquisition of cisplatin resistance of LUAD cells. The intracellular cAMP/PKA/CREB1 pathway upregulated MAFF in response to cisplatin-based or ionizing radiation treatments. MAFF suppresses tumor growth, and pharmacological agonists targeting MAFF may improve cisplatin or irradiation therapies for lung adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

Background: Limited resection has been carried out increasingly in early stage NSCLC as an alternative to standard lobectomy. This study aimed to investigate the differences in survival and long-term cause-specific mortality between wedge resection and segmentectomy for treatment of stage IA lung adenocarcinoma. Method: Cases with primary lung adenocarcinoma that received wedge resection and segmentectomy between 2004 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching was performed to balance the baseline covariates. Long-term cause-specific mortality was investigated through competing risk analysis. The overall survival (OS) was estimated with the Kaplan-Meier method with the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify the independent prognostic factors. Results: Of the 3,046 cases included, 2,360 and 686 cases underwent wedge resection and segmentectomy, respectively. After propensity score matching, 686 pairs were selected. Segmentectomy was associated with a significantly better OS in stage IA2, grade I/II, female, and married patients. The segmentectomy group had a higher lung-cancer specific mortality in 65–74 years of age, stage IA1 and IA3, male, and married patients, and a lower chronic obstructive pulmonary disease (COPD) specific mortality in ≤64 and 65–74 years of age, stage IA1, IA2, and IA3, all grade, male, and married patients. The cardiovascular disease (CVD) specific mortality was also lower in the segmentectomy group in ≥75 years of age, stage IA1 and IA3, and grade I/II patients. Conclusion: Wedge resection was inferior to segmentectomy in terms of OS regarding all included parameters. In most cases, the segmentectomy group had higher lung-cancer specific mortality and lower COPD and CVD specific mortality. [ABSTRACT FROM AUTHOR]