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

• DOI: 10.1016/j.celrep.2021.108772
• Publication Date: 2021-02-23T23:05:07Z
• Authors: Hiroyuki Tomita; Kaori Tanaka; Akihiro Hirata; Hideshi Okada; Hisashi Imai; Yohei Shirakami; Kotaro Ohnishi; Shigeyuki Sugie; Hitomi Aoki; Yuichiro Hatano; Kei Noguchi; Tomohiro Kanayama; Ayumi Niwa; Natsuko Suzui; Tatsuhiko Miyazaki; Takuji Tanaka; Haruhiko Akiyama; Masahito Shimizu; Kazuhiro Yoshida; Akira Hara
• Keywords: 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

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.