In vitro models of aneuploidy. Taylor, et al., Cancer Cell, 2018. Genomic and Functional Approaches to Understanding Cancer Aneuploidy.
Lung Cancer Biology
We match our discovery efforts with investigations into the functional consequences of the genome alterations we have reported in lung cancer.
To better understand the genetic basis of EGFR dependence, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. We found 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells. Our results showed that EGFR-independent survival is maintained by a convergence of PI3K-AKT and MEK-ERK signaling pathways (Sharifnia, et al., 2014).
In parallel with our genome discovery efforts, the Meyerson laboratory has also performed extensive cellular, biochemical, and functional genomic analyses of genes that are mutated in lung cancers. For example, in collaboration with the Bass laboratory we have demonstrated that SOX2 cooperates with p63 to promote survival of lung squamous cell carcinoma-derived cell lines (Watanabe, et al., 2014). This work reveals the impact of genomic amplification of SOX2, previously reported by our group, in squamous cell lung cancers. More recently, we have shed light on mechanisms by which mutations in RIT1 (Berger, et al., 2014) and MAP2K1 (Gannon, et al., 2016) promote oncogenic behaviors in cellular and animal models of cancer.
To enable accurate prediction of the function of mutated alleles in cancer, we have led a large-scale effort to validate the oncogenic potential and impact on cell behavior of hundreds of mutated alleles discovered in lung adenocarcinoma by us and others (Berger, et al, 2016). This method is termed eVIP (expression-based variant-impact phenotyping), and it uses gene expression changes to determine the functional impact of mutant alleles observed in cancer. The ability to distinguish oncogenic somatic gene alterations from neutral events, using a tool such as eVIP, could help identify promising targets for drug development.
Role of aneuploidy in human lung cancers. We developed a recombination-directed approach to generate chromosome aneuploidy and used this method to remove one copy of the chromosome arm 3p in human lung epithelial cells (Taylor, et al., 2018). We found that some of the resulting cells acquire an extra copy of chromosome 3 and are thus duplicated for the 3q arm (referred to as 3q gain). We have isolated cells carrying a 3q gain and are studying the role of these two aneuploidies, 3p loss and 3q gain, in lung squamous cell carcinoma.