Role of aberrant PI3K pathway activation in gallbladder tumorigenesis

Andrea Lunardi, Kaitlyn A. Webster, Antonella Papa, Bhavik Padmani, John G. Clohessy, Roderick T Bronson, Pier Paolo Pandolfi

Research output: Contribution to journalArticleResearchpeer-review

26 Citations (Scopus)

Abstract

The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,-trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to "trunkular" mutations.

Original languageEnglish
Pages (from-to)894-900
Number of pages7
JournalOncotarget
Volume5
Issue number4
DOIs
Publication statusPublished - 10 Mar 2014
Externally publishedYes

Keywords

  • Gallbladder tumorigenesis
  • Mouse model
  • PI3K
  • PTEN

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