Abstract
Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC) development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR) or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar-to-ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation-induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar-to-ductal conversion and PDAC initiation through direct transcriptional induction of Sox9. Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies with a 5-year survival rate of less than 7% [1]
NFATc4 Is Highly Induced during epidermal growth factor (EGFR)-Mediated Acinarto-Ductal Metaplasia
Pancreatic ductal adenocarcinoma (PDAC) represents a devastating disease with a dismal prognosis that has remained unchanged during the past several decades
Summary
Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies with a 5-year survival rate of less than 7% [1]. PDAC arises from well-defined precursor lesions, with pancreatic intraepithelial neoplasia (PanIN) being the best described [2, 3]. Oncogenic mutations of the Kras gene represent the defining molecular alteration in pancreatic carcinogenesis and can be detected in early PanIN lesions and in more than 90% of advanced human PDAC, leading to the current dogma that this genetic event is required for PDAC initiation and progression [4, 5]. Lineage-tracing studies have demonstrated that acinar cells expressing oncogenic Kras lose their grape-like structure and undergo a de- and transdifferentiation process termed acinar-to-ductal metaplasia (ADM) to generate metaplastic lesions with a duct-like phenotype [4, 5]. Oncogenic Kras hijacks the acinar redifferentiation process that occurs in regenerative pancreatic tissue and
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