ABSTRACT
Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) is clinically and genetically heterogeneous, with concurrent RB1/TP53 mutations, indicating an increased risk of transformation into small cell lung cancer (SCLC). When tumor cells convert into a different histological subtype, they lose their dependence on the original oncogenic driver, resulting in therapeutic resistance. However, the molecular details associated with this transformation remain unclear. It has been difficult to define molecular mechanisms of neuroendocrine (NE) transformation in lung cancer due to a lack of pre- and post-transformation clinical samples. In this study, we established a NSCLC cell line with concurrent RB1/TP53 mutations and built corresponding patient-derived xenograft (PDX) models to investigate the mechanisms underlying transformation to SCLC. Studying these PDX models, we demonstrate that EGFR loss facilitates lineage plasticity of lung adenocarcinoma initiated by biallelic mutations of TP53 and RB1. Gene expression analysis of these EGFR knockout tumors revealed altered expression of neuroendocrine synapse-associated lineage genes. There is an increased expression of epigenetic reprogramming factors like Sox2 and gene associated with neural development like NTRK in these EGFR knockout tumors. These findings uncovered the role of EGFR in the acquisition of plasticity, which is the ability of a cell to substantially modify its identity and take on a new phenotype, and defined a novel landscape of potential drivers of NE transformation in lung cancer.
Subject(s)
Adenocarcinoma of Lung , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Adenocarcinoma of Lung/pathology , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors/therapeutic use , Small Cell Lung Carcinoma/pathology , AnimalsABSTRACT
Colorectal cancer (CRC) is one of the most common tumors, ranking second in the global cause of death from cancer. The prognosis of advanced patients is still very poor. In this study, hub modules with the highest association with tumor-infiltrating immune cells were identified by weighted gene co-expression network analysis based on CRC expression data from the Gene Expression Omnibus database. Next, three hub genes (ADAM8, IL-1A, VAV3) related to infiltrating immune cells were identified by co-expression network and prognostic analysis. After analysis and verification of the TIMER database, ADAM8 was selected as a prognostic biomarker. Finally, the result of functional test showed that ADAM8 gene expression down-regulation partially reversed the immune tolerance of CRC cells to TILs. By bioinformatics analysis methods and the experimental techniques, we identified ADAM8 as a prognostic biomarker and clinical therapeutic target related to tumor-infiltrating immune cells in CRC.
Subject(s)
Biomarkers, Tumor/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Lymphocytes, Tumor-Infiltrating/immunology , ADAM Proteins/genetics , Cell Death , Cell Line, Tumor , Colorectal Neoplasms/pathology , Gene Knockdown Techniques , Genes, Neoplasm , Humans , Membrane Proteins/genetics , Prognosis , Reproducibility of Results , Signal Transduction/geneticsABSTRACT
OBJECTIVE: To analyze the clinicopathological characteristics and prognostic factors of multifocal lung cancer (MFLC) patients. METHODS: From January 2012 to January 2018, 187 MFLC patients whose largest lesion diameter was ≤4 cm and without lymphatic involvement or systemic metastases, were retrospectively reviewed. All the patients received surgical treatment. The Kaplan-Meier method was used for survival analysis, and a multivariable Cox proportional hazards regression model was used to assess the independent prognostic factors. RESULTS: Among 187 cases, 173 were simultaneous MFLC (SMFLC) and 14 were metachronous MFLC (MMFLC). The 5-year disease-free survival (DFS) and overall survival (OS) rates of this group MFLC patients were 63.5% and 89.1%, respectively. In the SMFLC group, according to the American College of Chest Physicians (ACCP) guidelines (3 rd edition), 133 patients were defined as synchronous multiple primary lung cancer (SMPLC) while 40 patients had intrapulmonary metastases, there was no statistical difference in DFS between the two subgroups ( P=0.531). EGFR mutation status (same mutations, different mutations, all wild-type) had no statistically significant effect on DFS of SMFLC ( P=0.388). Univariate and multivariate regression analysis revealed that radiographic feature of solid nodules (hazard ratio ( HR)=7.4, P=0.008) and MMFLC ( HR=5.6, P=0.001) were independent risk factors for poor prognosis. CONCLUSION: MFLC can achieve a favorable prognosis with early surgical treatment. Tumor density and metachronous lesions are two important prognostic predictors.
