TY - JOUR TI - FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer AU - Camolotto, Soledad A AU - Pattabiraman, Shrivatsav AU - Mosbruger, Timothy L AU - Jones, Alex AU - Belova, Veronika K AU - Orstad, Grace AU - Streiff, Mitchell AU - Salmond, Lydia AU - Stubben, Chris AU - Kaestner, Klaus H AU - Snyder, Eric L A2 - White, Richard M A2 - Settleman, Jeffrey VL - 7 PY - 2018 DA - 2018/11/26 SP - e38579 C1 - eLife 2018;7:e38579 DO - 10.7554/eLife.38579 UR - https://doi.org/10.7554/eLife.38579 AB - Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. Foxa1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, we observe downregulation of FoxA1/2 expression in the squamous component of both murine and human lung adenosquamous carcinoma. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia originating from SPC-positive alveolar cells induces keratinizing squamous cell carcinomas. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung cancer in a context-specific manner. KW - FoxA1 KW - FoxA2 KW - NKX2-1 KW - lineage switching KW - lung cancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -