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

Cell Rep. 2021 Feb 23;34(8):108772. doi: 10.1016/j.celrep.2021.108772.

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.

Keywords: bile duct stem/progenitor cell; cholangiocarcinoma; fibroblast growth factor 10; intraductal papillary neoplasm of the bile duct; peribiliary gland.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / pharmacology
  • Bile Duct Neoplasms / drug therapy
  • Bile Duct Neoplasms / enzymology*
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / pathology
  • Carcinoma, Papillary / drug therapy
  • Carcinoma, Papillary / enzymology*
  • Carcinoma, Papillary / genetics
  • Carcinoma, Papillary / pathology
  • Cells, Cultured
  • Cholangiocarcinoma / drug therapy
  • Cholangiocarcinoma / enzymology*
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / pathology
  • Disease Progression
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Fibroblast Growth Factor 10 / genetics
  • Fibroblast Growth Factor 10 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Genes, ras
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, Transgenic
  • Middle Aged
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation
  • Neoplastic Stem Cells / enzymology*
  • Neoplastic Stem Cells / pathology
  • Phosphorylation
  • Precancerous Conditions / drug therapy
  • Precancerous Conditions / enzymology*
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • FGF10 protein, human
  • Fgf10 protein, mouse
  • Fibroblast Growth Factor 10
  • Protein Kinase Inhibitors
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases