| First Author | Orstad G | Year | 2022 |
| Journal | Dev Cell | Volume | 57 |
| Issue | 15 | Pages | 1866-1882.e10 |
| PubMed ID | 35835117 | Mgi Jnum | J:327356 |
| Mgi Id | MGI:7331282 | Doi | 10.1016/j.devcel.2022.06.017 |
| Citation | Orstad G, et al. (2022) FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma. Dev Cell 57(15):1866-1882.e10 |
| abstractText | Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in many cancers, including lung adenocarcinoma (LUAD). The lineage-specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) control identity in NKX2-1/TTF1-negative LUAD. However, their role in NKX2-1-positive LUAD has not been systematically investigated. We find that Foxa1/2 knockout severely impairs tumorigenesis in KRAS-driven genetically engineered mouse models and human cell lines. Loss of FoxA1/2 leads to the collapse of a dual-identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, which has been implicated in LUAD progression. Mechanistically, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic localization, which in turn actively inhibits tumorigenesis and drives alternative cellular identity programs that are associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease. |
