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

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. H3K27ac ChIP-seq was performed using antibody recognizing endogenous protein with input genomic DNA as control with/without transduction of sgNEG/sgTP63#2/sgTP63#4 (BxPC3 cells) or MTV/TP63ΔN (SUIT2 cells). TP63 ChIP-seq in BxPC3 cells was performed using antibody recognizing endogenous protein with input genomic DNA as control. FLAG-TP63 ChIP-seq in SUIT2 cells was performed in FLAG-TP63 expressing cells with input genomic DNA as control.