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

Dev Cell. 2022 Aug 8;57(15):1866-1882.e10. doi: 10.1016/j.devcel.2022.06.017. Epub 2022 Jul 13.

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.

Keywords: FoxA1; FoxA2; NKX2-1; cellular identity; lineage switching; lung adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma* / genetics
  • Adenocarcinoma* / metabolism
  • Animals
  • Cell Transformation, Neoplastic
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Humans
  • Lung Neoplasms* / metabolism
  • Mice
  • Thyroid Nuclear Factor 1

Substances

  • FOXA1 protein, human
  • FOXA2 protein, human
  • Foxa1 protein, mouse
  • Foxa2 protein, mouse
  • Hepatocyte Nuclear Factor 3-alpha
  • NKX2-1 protein, human
  • Thyroid Nuclear Factor 1
  • Hepatocyte Nuclear Factor 3-beta