Lung adenocarcinoma accounts for about 40% of all lung cancers and is the most common form of lung cancer found in women and in people under the age of forty-five. Strikingly, the 5-year survival rate for lung cancer overall is only about 18 percent, and more than half of people with lung cancer die within one year of diagnosis. This highlights the need for more effective treatment options and underscores the importance of research focused on uncovering and understanding new molecular and cellular pathways that contribute to lung cancer biology. Messenger RNAs (mRNAs) are subject to various posttranscriptional modifications including N6-Methyladenosine (m6A). m6A is the most abundant mRNA modification and is emerging as an important regulator of gene expression that can affect mRNA splicing, export, stability, and translation. m6A is catalyzed the METTL3 methyltransferase complex, and occurs at a characteristic sequence motif at a position close to the translation stop codon of a large subset of mRNAs. The goal of this proposal is to test the central hypothesis that METTL3 is a novel oncogenic factor in lung cancer. The global m6A mRNA `epitranscriptome' will be mapped and measured in a cohort of primary human lung tumor samples. Relative levels of METTL3 in tumors will be measured by immunohistochemistry and correlated with the m6A levels and transcriptome-wide distribution. Loss- and gain-of-function experiments will address the widespread impact of METTL3 (and METTL3-interacting proteins) in controlling target mRNA expression, and will help uncover the molecular and cellular role of METTL3, METTL3-interacting proteins, and a selection of downstream targets mRNAs, in lung cancer cell biology. Finally, the effects of METTL3 manipulation in lung tumor initiation and progression will be explored using a mouse lung cancer model, as well as a novel lung organoid model and a panel of assays will be deployed to examine the underlying molecular mechanism. Successful completion of the proposed studies will help establish METTL3 as a possible future therapeutic target for lung adenocarcinoma and other cancers.
This study will characterize messenger RNA (mRNA) methylation in lung tumors and explore the oncogenic role of the RNA methyltransferase METTL3 in lung cancer. This investigation could lead to novel therapeutic strategies to control oncogene expression in lung adenocarcinoma and other tumor types. 1
