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

Orstad, Grace, Fort, Gabriela, Parnell, Timothy J, Jones, Alex, Stubben, Chris, Lohman, Brian, Gillis, Katherine L, Orellana, Walter, Tariq, Rushmeen, Klingbeil, Olaf, Kaestner, Klaus, Vakoc, Christopher R, Spike, Benjamin T, Snyder, Eric L (July 2022) FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma. Developmental Cell. ISSN 1534-5807

DOI: 10.1016/j.devcel.2022.06.017


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.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
diseases & disorders > neoplasms
organism description > animal
diseases & disorders > cancer > cancer types > lung cancer
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
organism description > animal > mammal > rodent
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Vakoc lab
CSHL Cancer Center Program
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 5 July 2022
Date Deposited: 27 Jul 2022 04:23
Last Modified: 09 Feb 2024 20:14
PMCID: PMC9378547

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