腺泡细胞在经历腺泡到导管化生（ADM）后被提议作为胰腺导管腺癌（PDAC）的起源细胞。 ADM 可由胰腺炎触发，导致腺泡细胞去分化为导管样状态。我们确定 FRA1（基因名称 Fosl1）是 KrasG12D 急性胰腺炎介导的损伤期间最活跃的转录因子，并且我们通过生成表达 KrasG12D 的腺泡特异性 Fosl1 敲除小鼠，阐明了 FRA1 的功能作用。使用从单核 ATAC-seq 和批量 RNA 测序 (RNA-seq) 推断的基因调控网络和伪时间轨迹，我们假设了腺泡-ADM-胰腺上皮内瘤变 (PanIN) 连续体的调控模型，并通过实验验证了 Fosl1 敲除小鼠 ADM 和肿瘤转化的发生被延迟。我们的研究还发现促炎细胞因子，例如粒细胞集落刺激因子 (G-CSF)，可以调节 FRA1 活性以调节 ADM。我们的研究结果表明，FRA1 是腺泡细胞可塑性的介质，对于腺泡细胞去分化和转化至关重要。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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 sequencing (RNA-seq), we hypothesized a regulatory model of the acinar-ADM-pancreatic intraepithelial neoplasia (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 granulocyte colony stimulating factor (G-CSF), can regulate FRA1 activity to modulate ADM. Our findings identify that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation.Copyright © 2024 Elsevier Inc. All rights reserved.