Lunardi, AndreaWebster, Kaitlyn A.Papa, AntonellaPadmani, BhavikClohessy, JohnBronson, RoderickPandolfi, Pier Paolo2014-07-072014Lunardi, Andrea, Kaitlyn A. Webster, Antonella Papa, Bhavik Padmani, John G. Clohessy, Roderick T. Bronson, and Pier Paolo Pandolfi. 2014. “Role of aberrant PI3K pathway activation in gallbladder tumorigenesis.” Oncotarget 5 (4): 894-900.1949-2553http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407044The 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.en-USPI3KPTENgallbladder tumorigenesismouse modelJournal Article2014-07-0710.18632/oncotarget.1808