Dr. Watanabe has investigated the role of oncogenic lineage-specific transcriptional regulators in non-small cell lung cancer. He co-led the discovery of SOX2 as the most commonly amplified oncogenes (10~15%) in lung squamous cell carcinomas using SNP array analysis of somatic copy number alterations (Bass, Watanabe et al., Nat Genet 2009). In lung adenocarcinoma, another principal subtype of lung cancer, NKX2-1 is the most commonly amplified gene. These two transcription factors may exert similar oncogenic roles in their respective tumor types and our group proposed that they act as lineage-survival oncogenes in lung cancer. Sox2, a prominent embryonic stem cell transcription factor, has also been demonstrated to play an essential role later in development in the specification of the squamous cell lineages. Nkx2-1, a master regulator of lung morphogenesis opposes the role of Sox2 by specifying the lung lineages from dividing foregut. Dr. Watanabe has explored their mechanisms of action using functional genomic approaches, identifying p63 transcription factor as a novel and specific partner of Sox2 in squamous cell cancers through comparative cistromic analyses and functional proteomics (Watanabe, Ma et al., JCI 2014) and identifying an oncogenic transcriptional regulator, LMO3 as a functional target of Nkx2-1 in cooperation with FoxA1 transcription factor in lung adenocarcinoma (Watanabe et al., Genes Dev 2013). Further, in collaboration with the Tyler Jacks’ laboratory, he has determined Nkx2-1 is also required for proper FoxA1/FoxA2 localization and implicated a global change in FoxA1/FoxA2 binding as a critical step in the transition from a pulmonary to a gut differentiation state in a murine model of lung adenocarcinoma (Snyder, Watanabe et al., Mol Cell 2013).