Cancer is a multistep process that involves alterations in cell-autonomous and non-cell autonomous events that are modulated by metabolic factors. Our laboratory uses genetically engineered mouse models (GEMMs) of lung cancer, which recapitulate the genetics, histological progression and tissue microenvironment, to elucidate the interactions of tumor cell autonomous oncogenic events with alterations in tumor and whole-animal metabolism (Papagiannakopoulos, T. et al, Cell Metabolism, 2016). We recently pioneered novel CRISPR/Cas9-based somatic genome engineering in lung cancer GEMMs (Sánchez-Rivera, F. J. and Papagiannakopoulos, T. et al, Nature 2014). Using CRISPR/Cas9-based genome engineering, we have developed a platform to rapidly characterize the function of genes which are highly mutated in lung cancer, elucidate their mechanism of action and identify novel targeted therapies against complex genetic subtypes of lung cancer. 

A major focus of our laboratory is to apply CRISPR/Cas9-based in vivo and in vitro approaches to study KRAS-driven lung cancer, the major subtype of lung cancer and one of the most aggressive and lethal solid tumors. Therapeutic options and outcomes for KRAS-driven cancers have remained virtually unchanged over the past thirty years. Specifically, we are investigating how genetic alterations in the metabolic pathways (e.g. NRF2/KEAP1, LKB1), which are observed in a large subset of lung cancers, can influence tumor initiation and progression by rewiring metabolic pathways. We use a combination of genetic and biochemical approaches to identify metabolic liabilities that can be exploited using novel targeted therapies. Since the establishment of our laboratory in October 2015, we have made significant progress in applying our approaches to characterize a major genetic subset of lung adenocarcinoma with NRF2/KEAP1 mutations (Ashouri et al., Nat. Comm, 2017; In Press: Romero R et al., Nature Medicine; Sayin VI et al., eLife).