FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma.

ABSTRACT: 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.

SUBMITTER: Orstad G 

PROVIDER: S-EPMC9378547 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature