New Mouse Models for Identifying Driver Mutations in Human Squamous Cell Lung Cancer

Background and objectives: Human squamous cell lung cancer (SCC) is the second most common lung cancer subtype and is strongly associated with smoking in a dose-dependent manner. Surgery is not an option for most SCC patients since the disease usually has spread at the time of diagnosis. All of these issues highlight an unmet need to identify new functional (driver) mutations in SCC thus enabling the design of new therapies and/or enhancing current treatments. Research goal: The primary goal of this proposal is to establish a new platform to identify functional mutations that contribute to squamous cell lung cancer in patients who are mostly smokers. This information is critical for precision medicine since therapies (including targeted therapies and immunotherapies) can then be tailored for a given patient. Preliminary results: Many mutations have been uncovered from genomic analysis of human cancer but no assays are currently available to systematically test their functional roles in tumor development in vivo. As such, the genomic information has not been as useful as it could be in guiding precision treatment. Our proposal will overcome this major hurdle by screening for human driver mutations specific to squamous cell lung cancer. Our ultimate goal is to establish a universal method to rapidly and quantitatively identify new driver mutations in squamous cell lung cancer. Research designs: I will combine tumor barcoding coupled with barcode sequencing (Tuba-seq), CRISPR technology, and a sensitized mouse model of squamous cell lung cancer in this proposal. Aim 1: To identify new oncogenes for squamous cell lung cancer through their overexpression and accelerated tumor development in mouse models. Aim 2: To discover new tumor suppressors for squamous cell lung cancer by their inactivation and enhanced tumor development in mouse models. Aim 3: To recapitulate all mutations from a given squamous cell lung cancer patient in a single mouseNovelty and application:Our main goal of this application is to identify functional mutations for squamous cell lung cancer patients. If drugs are available to target directly the genes identified or indirectly the downstream cascades, they can provide new therapies. If no drugs are available to modulate the activity of genes identified, they are novel targets for drug development.Milestones:(1) Overexpress candidate oncogenes in mice carrying a sensitized genetic background for squamous cell lung cancer; (2) Perform Tuba-seq on squamous cell lung tumors to identify dominant oncogenes that contribute to accelerated tumor development; (3) Eliminate candidate tumor suppressors in mice carrying a sensitized genetic background for squamous cell lung cancer to search for new tumor suppressors; (4) Perform Tuba-seq on squamous cell lung tumors to identify tumor suppressors that contribute to accelerated tumor development.