Project description:Lung adenocarcinoma (LUAD) is one of the deadliest malignancies worldwide. Dynamic lineage changes within the lung epithelium and the high plasticity of these epithelial cells confound the correct identification of the cell-of-origin of LUAD. Here, we combined lineage-tracing mouse models with an autochthonous cell type-independent LUAD model in order to discover the cellular origin of ALK-translocated LUAD. We identified Club and AT2 cells as the cells-of-origin of LUAD. Moreover, we uncovered epigenetic imprints in the tumours originating from Club or AT2 cells by whole-genome bisulfite sequencing. Single-cell transcriptomes of Club cells at different stages of tumour development identified two trajectories of Club cell evolution. On both routes, tumours lose their Club cell identity and gain an AT2-like phenotype. Together, this study highlights the role of Club cells in LUAD initiation and unveils key mechanisms conferring LUAD heterogeneity.
Project description:Lung adenocarcinoma (LUAD) is one of the deadliest malignancies worldwide. Dynamic lineage changes within the lung epithelium and the high plasticity of these epithelial cells confound the correct identification of the cell-of-origin of LUAD. Here, we combined lineage-tracing mouse models with an autochthonous cell type-independent LUAD model in order to discover the cellular origin of ALK-translocated LUAD. We identified Club and AT2 cells as the cells-of-origin of LUAD. Moreover, we uncovered epigenetic imprints in the tumours originating from Club or AT2 cells by whole-genome bisulfite sequencing. Single-cell transcriptomes of Club cells at different stages of tumour development identified two trajectories of Club cell evolution. On both routes, tumours lose their Club cell identity and gain an AT2-like phenotype. Together, this study highlights the role of Club cells in LUAD initiation and unveils key mechanisms conferring LUAD heterogeneity.
Project description:The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening system in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smoke-related lung tumors in the A/J mouse using transcriptomics and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression analysis of lung tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m3 MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis illustrated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene signature and show its utility in distinguishing between the cigarette smoke-related and spontaneous lung tumors.
Project description:The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening system in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smoke-related lung tumors in the A/J mouse using transcriptomics and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression analysis of lung tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m3 MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis illustrated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene signature and show its utility in distinguishing between the cigarette smoke-related and spontaneous lung tumors.
