Journal
CELL REPORTS
Volume 34, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.108772
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- JSPS KAKENHI [JP 12891150]
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The study demonstrates that FGF10-induced IPNB in mice mimics human IPNB phenotypes, with a pathway involving FGF10-FGFR2-RAS-ERK. Inhibition of this pathway suppresses papillary changes and progression of IPNB, making it a potential therapeutic target.
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 Kras(G12D), 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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