Morphogenesis and regeneration share a conserved core transition cell state program that control lung epithelial cell fate
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE254356 | GEO | 2024/06/01
REPOSITORIES: GEO
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Project description:Morphogenesis and regeneration share a conserved core transition cell state program that control lung epithelial cell fate
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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)
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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.
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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.
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