GSE115899
FoxA1 and FoxA2 are required for gastric differentiation in NKX2-1-negative lung adenocarcinoma [total RNA-seq analysis]
Profound 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, stochastic loss of FoxA1/2 expression in NKX2-1-negative tumors is associated with keratinizing squamous differentiation.  Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia is sufficient for direct induction of keratinizing squamous cell carcinomas in the lung. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung adenocarcinoma in a context-specific manner. Overall design: Murine lung tumor cells of differing genotypes were isolated by FACS and subjected to total RNA-Seq.