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FoxA1 and FoxA2 are required for gastric differentiation in NKX2-1-negative lung adenocarcinoma

ABSTRACT: FoxA1 and FoxA2 are required for gastric differentiation in NKX2-1-negative lung adenocarcinoma

PROVIDER: PRJNA476402 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7350080.fastq.gz	Fastqsanger.gz
	SRR7350090.fastq.gz	Fastqsanger.gz
	SRR7350100.fastq.gz	Fastqsanger.gz
	SRR7350110.fastq.gz	Fastqsanger.gz
	SRR7350120.fastq.gz	Fastqsanger.gz

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

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

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

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

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

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

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

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

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

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

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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)

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

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