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TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (RNA-seq)

ABSTRACT: TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (RNA-seq)

PROVIDER: PRJNA475110 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7276360.fastq.gz	Fastqsanger.gz
	SRR7276370.fastq.gz	Fastqsanger.gz
	SRR7276361.fastq.gz	Fastqsanger.gz
	SRR7276371.fastq.gz	Fastqsanger.gz
	SRR7276362.fastq.gz	Fastqsanger.gz

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TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma

Project description:The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative trans-differentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔN isoform) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. In addition, we demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion and an accelerated growth of primary PDA tumors and metastases in vivo. Conversely, we provide evidence that squamous PDA remains addicted to TP63 to sustain the growth of primary tumors and metastases. Taken together, our study validates the functional significance of squamous trans-differentiation in PDA, and reveals TP63-based reprogramming of PDA cells as an experimental tool for investigating vulnerabilities linked to this cell fate transition.

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TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma.

Project description:The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (?Np63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition.

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