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.
More...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.
Overall design: Refer to individual Series
Less...| Accession | PRJNA475105; GEO: GSE115463 |
| Type | Umbrella project |
| Publications | Somerville TDD et al., "TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma.", Cell Rep, 2018 Nov 13;25(7):1741-1755.e7 |
| Submission | Registration date: 7-Jun-2018
Vakoc, CSHL, Cold Spring Harbor Laboratory |
| Relevance | Superseries |
Project Data:
| Resource Name | Number
of Links |
|---|
| Sequence data |
| SRA Experiments | 92 |
| Publications |
| PubMed | 1 |
| PMC | 1 |
| Other datasets |
| BioSample | 92 |
| GEO DataSets | 3 |
TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma encompasses the following 2 sub-projects:
| Project Type | Number of Projects |
| Epigenomics | 1 |
BioProject
accession | Organism | Title |
|---|
| PRJNA475111 | Homo sapiens | TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (ChIP-seq) (Vakoc, CSHL, Cold Spring...) |
|
| Transcriptome or Gene expression | 1 |
BioProject
accession | Name | Title |
|---|
| PRJNA475110 | TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (RNA-seq) | TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (RNA-seq) (Vakoc, CSHL, Cold Spring...) |
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