Abstract
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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.