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FoxA1 and FoxA2 are required for gastric differentiation in NKX2-1-negative lung adenocarcinoma [single cell analysis]

ABSTRACT: Profound 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, stochastic loss of FoxA1/2 expression in NKX2-1-negative tumors is associated with keratinizing squamous differentiation. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia is sufficient for direct induction of keratinizing squamous cell carcinomas in the lung. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung adenocarcinoma in a context-specific manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE115900 | GEO | 2018/12/16

REPOSITORIES: GEO

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FoxA1 and FoxA2 are required for gastric differentiation in NKX2-1-negative lung adenocarcinoma [total RNA-seq analysis]

Project description:Profound 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, stochastic loss of FoxA1/2 expression in NKX2-1-negative tumors is associated with keratinizing squamous differentiation. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia is sufficient for direct induction of keratinizing squamous cell carcinomas in the lung. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung adenocarcinoma in a context-specific manner.

2018-12-16 | GSE115899 | GEO

Nkx2.1 represses a latent gastric differentiation program in lung adenocarcinoma

Project description:During cancer evolution, cellular differentiation programs become dysregulated. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to study the fate of lung epithelial cells upon loss of their master cell fate regulator. Nkx2-1 deletion in normal and neoplastic lung causes not only loss of pulmonary identity but also gastric transdifferentiation. Nkx2-1 maintains pulmonary identity by sequestering the Foxa1 transcription factor at lung-specific loci and inhibiting Foxa1 binding to gastrointestinal targets. Murine Nkx2-1-negative lung tumors mimic the mucinous subtype of human lung adenocarcinoma, which also exhibits gastric transdifferentiation. Nkx2-1-negative lung adenocarcinomas are dependent on the gastrointestinal gene Hnf4a for efficient initiation. Thus, loss of Nkx2-1 results in transdifferentiation rather than stable dedifferentiation in vivo, suggesting that inactivation of both active and latent differentiation programs may be required for tumors to reach a primitive, dedifferentiated state. The study was designed to compare the expression profiles of Nkx2-1-positive lung adenocarcinomas with tumors in which Nkx2-1 was deleted at the time of initiation or 6-7 months after initiation.

2013-04-10 | E-GEOD-36473 | biostudies-arrayexpress

Nkx2-1 Represses a Latent Gastric Differentiation Program in Lung Adenocarcinoma

Project description:Tissue-specific differentiation programs become dysregulated during cancer evolution. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to study the fate of lung epithelial cells upon loss of their master cell fate regulator. Nkx2-1 deletion in normal and neoplastic lung causes not only loss of pulmonary identity but also gastric transdifferentiation. Nkx2-1 maintains pulmonary identity by sequestering the Foxa1 transcription factor at lung-specific loci and by inhibiting Foxa1 binding to gastrointestinal targets. Murine Nkx2-1-negative lung tumors mimic the mucinous subtype of human lung adenocarcinoma, which also exhibits gastric transdifferentiation. Nkx2-1-negative lung adenocarcinomas are dependent on the gastrointestinal gene Hnf4a for efficient initiation. Thus, loss of Nkx2-1 causes transdifferentiation rather than stable dedifferentiation in vivo, suggesting that inactivation of both active and latent differentiation programs are required for tumors to reach a primitive, dedifferentiated state. ChIP-seq data from murine lung adenocarcinomas on (i) transcription factors Nkx2-1 and Foxa in Nkx2-1-deleted tumors and Nkx2-1-positive control tumors, and (ii) four histone marks in Nkx2-1-deleted tumors and Nkx2-1-positive control tumors. (All samples in duplicate and with input controls, i.e. (2 x [(3+3) + (2+8)]) - 1 = 31 samples total - 1 input control used for transcription factor and histone mark, GSM1059357)

2013-04-09 | E-GEOD-43252 | biostudies-arrayexpress

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (bulk RNA-Seq)

Project description:Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in multiple types of cancer, including lung adenocarcinoma (LUAD). The lineage specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) regulate 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. Foxa1/2 deletion leads to collapse of a dual-identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, that has been implicated in LUAD progression. Mechanistically, loss of FoxA1/2 leads to aberrant NKX2-1 activity and genomic localization, which inhibits tumorigenesis and drives alternative cellular identity programs associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a novel lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease.

2022-06-08 | GSE188435 | GEO

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (ChIP-Seq)

2022-06-08 | GSE188434 | GEO

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (scRNA-Seq)

2022-06-08 | GSE188436 | GEO

Nkx2.1 represses a latent gastric differentiation program in lung adenocarcinoma

2013-04-10 | GSE36473 | GEO

Nkx2-1 Represses a Latent Gastric Differentiation Program in Lung Adenocarcinoma

2013-04-09 | GSE43252 | GEO

RNA-seq analyses of mouse embryonic fibloblasts (MEFs) reprogrammed into induced pulmonary epithelial cell-like cells

Project description:RNA-seq analyses of MEFs obtained from GFP/SP-C transgenic mice on CBA/Ca x C57BL/6 mixed background were transduced sets of 3 or 4 combination factors (Nkx2-1/Foxa1/Gata, Nkx2-1/Foxa2/Gata, Nkx2-1/Foxa1/Foxa2/Gata6) into induced pulmonary epithelial cell-like cells 14 days after the transduction. Abstract is as follows: pneumocyte differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells. However, direct reprograming of somatic cells into pulmonary epithelial cells has not been achieved. Here, we report that a combination of three or four transcription factors (i.e., Nkx2-1, Gata6, and [Foxa1 and/or Foxa2]) directly reprogrammed mouse tail-tip fibroblast or embryonic fibroblast into differentiated induced pulmonary epithelial cell-like cells (iPUL cells). iPUL cells had a global gene expression profile similar to various kinds of pulmonary epithelial cells. Some iPUL cells showed lamellar body-like structures and expressed SP-C, consistent with the features of alveolar epithelial type II cells. Interestingly, intratracheal administration of iPUL cells rescued influenza virus-induced acute lung injury in mice. These findings demonstrate that functional pulmonary epithelial cell-like cells can be directly reprogrammed from differentiated somatic cells by defined factors. Reprograming of fibroblasts might provide a source of pulmonary epithelial cells for regenerative medicine. Publicly available raw RNA-seq data (GSE80101) representing whole mouse lung (SRR3353494, SRR3353497, SRR3353498) and alveolar type II cells (SRR3353495, SRR3353500, SRR3353510, SRR3353512) sorted in the basis of EpCAM+ and dTomato+ from SpcCreERT2;RosatdTomato mice were also simultaneously processed with our data.

2023-06-30 | GSE109810 | GEO

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.

Project description:Cancer cells often undergo lineage switching during their natural progression and in response to therapy. Lung adenocarcinomas (LUADs) exhibit a variety of differentiation states accompanied by dysregulation of lineage-specific transcription factors such as NKX2-1. Loss of NKX2-1 in human and murine LUAD leads to invasive mucinous adenocarcinoma (IMA), a subtype of lung cancer that exhibits pulmonary to gastric transdifferentiation. Human IMAs harbor a distinct spectrum of mutationally activated driver oncogenes compare to LUAD overall, suggesting that the pulmonary to gastric transdifferentiation induced by NKX2-1 loss plays a context-dependent role in LUAD progression. Using genetically engineered mouse models, we find that NKX2-1 is required for optimal BRAFV600E driven lung tumor initiation but is dispensable for growth of established lung tumors. NKX2-1-deficient, BRAFV600E driven tumors morphologically resemble human IMA, have high levels of ERK phosphorylation and exhibit a distinct response to treatment with combined BRAF/MEK inhibitors. Whereas NKX2-1-positive tumor cells enter quiescence when treated with BRAF/MEK inhibitors, residual NKX2-1-negative cells fail to exit the cell cycle in response to the same therapy. Additionally, BRAF/MEK inhibitors induce canonical WNT signaling in NKX2-1-negative lung tumor cells, which is accompanied by cell identity switching within the gastric lineage. Co-inhibition of MAPK and WNT pathways blocked elements of this lineage switch in vitro and interfered with cell cycle changes imposed by MAPK inhibition in vivo. Our data show that there is a complex and reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of LUAD identity and suggest that lineage switching induced by targeted therapies may confer new therapeutic vulnerabilities.

2021-04-27 | GSE145152 | GEO

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