Original WB Li et. al. Developmental Cell

Published: 11 June 2024| Version 1 | DOI: 10.17632/n2c46ds4gn.1


Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar to ductal metaplasia (ADM). ADM can be triggered by pancreatitis causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during KrasG12D acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D. Using a gene regulatory network and pseudotime trajectory inferred from single nuclei ATAC-seq and bulk-RNA seq, we hypothesized a regulatory model of the acinar-ADM-PanIN continuum and experimentally validated that Fosl1 knockout mice are delayed in the onset of ADM and neoplastic transformation. Our study also identifies that pro-inflammatory cytokines, such as G-CSF, can regulate FRA1 activity to modulate ADM. Our findings reveal that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation.



Columbia University


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