Author/Authors :
Hingorani، نويسنده , , Sunil R. and Petricoin III، نويسنده , , Emanuel F. and Maitra، نويسنده , , Anirban and Rajapakse، نويسنده , , Vinodh and King، نويسنده , , Catrina and Jacobetz، نويسنده , , Michael A. and Ross، نويسنده , , Sally and Conrads، نويسنده , , Thomas P. and Veenstra، نويسنده , , Timothy D. and Hitt، نويسنده , , Ben A. and Kawaguchi، نويسنده , , Yoshiya and Johann، نويسنده , , Don and Liotta، نويسنده , , Lance A. and Crawford، نويسنده , , Howard C. and Putt، نويسنده , , Mary E. and Jacks، نويسنده , , Tyler and Wright، نويسنده , , Christopher V.E. and Hruban، نويسنده , , Ralph H. and Lowy، نويسنده , , Andrew M. and Tuveson، نويسنده , , David A.، نويسنده ,
Abstract :
To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRASG12D to progenitor cells of the mouse pancreas. We find that physiological levels of KrasG12D induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.
