Project description:We aimed to analyze the transcriptional profile of full-blown murine lung adenocarcinomas driven by K-RasG12V oncogene. We used a GEM model of lung adenocarcinoma driven by a resident K-RasG12V oncogene. On average, tumors were collected 10 months after Adeno-CRE infection.
Project description:Lung cancer is still the leading cause of cancer-related deaths in the US and worldwide. Understanding the global molecular profiles or transcriptome of lung cancers would strengthen our understanding of the biology of this malignancy. We performed gene expression profiling using the Human Gene 1.0 ST platform of 80 lung adenocarcinomas and 30 normal lung tissues to better understand the biology of this significant fraction of non-small cell lung carcinomas (NSCLCs) Lung adenocarcinomas were comrpised of never-smoker (n=40) and smoker (n=40) adenocarcinomas. Normal lung tissue (n=30) were paired to 30 of the never-smoker cases. Gene expression profiling was performed on the samples to identify differentially expressed profiles between lung adenocarcinomas and normal lung tissues.
Project description:Series of stage IB lung adenocarcinomas and large cell carcinomas. The aim of the study was to predict outcome using a Copy Number Driven Gene Expression signature. Experiment Overall Design: Homogeneous series of 72 cases of lung primary stage IB adenocarcinomas/large cell carcinomas, analyzed using the Human U133Plus 2.0 oligonucleotide arrays (Affymetrix, Santa Clara, CA).
Project description:As a master regulator of chromatin structure and function, the EZH2 lysine methyltransferase orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non- small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 has proven elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with a new genetically-engineered mouse model of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways leading to epigenetic transformation independent from canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a novel and potent EZH2 inhibitor that arises from a facile synthesis and possesses improved pharmacologic properties. JQEZ5 promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a defined subset of lung cancer. ChIP-Seq for H3K27ac and H3K27me3 in murine normal and EZH2 overexpressed tumor lung tissue
Project description:Accumulation of senescent cells in the tumour microenvironment can drive tumourigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumours. Single cell transcriptomics identify a population of tumour-associated macrophages, expressing a unique array of pro-tumourigenic SASP factors and surface proteins, that are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, and macrophage depletion, result in a significant reduction in tumour burden and increased mouse survival of KRAS-driven lung cancer models. Of translational relevance, we reveal the presence of macrophages with senescent features in human lung premalignant lesions, but not in adenocarcinomas. Together, our results have uncovered a population of senescent macrophages contributing to the initiation and progression of lung cancer, thus opening potential therapeutic avenues and cancer preventative strategies.