Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas

Male 0301 basic medicine QH301-705.5 Mice, Nude Antineoplastic Agents bile duct stem/progenitor cell Cholangiocarcinoma Mice 03 medical and health sciences peribiliary gland Animals Humans Biology (General) Extracellular Signal-Regulated MAP Kinases Cells, Cultured Aged Aged, 80 and over Mice, Inbred BALB C fibroblast growth factor 10 Carcinoma, Papillary 3. Good health Gene Expression Regulation, Neoplastic Mice, Inbred C57BL Genes, ras intraductal papillary neoplasm of the bile duct Bile Duct Neoplasms Disease Progression Female cholangiocarcinoma Fibroblast Growth Factor 10
DOI: 10.1016/j.celrep.2021.108772 Publication Date: 2021-02-23T23:05:07Z
ABSTRACT
Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With KrasG12D, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.
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