Pten constrains centroacinar cell expansion and malignant transformation in the pancreas

Ben Z. Stanger, Bangyan Stiles, Gregory Y. Lauwers, Nabeel Bardeesy, Michael Mendoza, Ying Wang, Amy Greenwood, Kuang Hung Cheng, Margaret McLaughlin, Dennis Brown, Ronald A. DePinho, Hong Wu, Douglas A. Melton, Yuval Dor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

239 Scopus citations

Abstract

To determine the role of the phosphatidylinositol 3-kinase (PI3-K) pathway in pancreas development, we generated a pancreas-specific knockout of Pten, a negative regulator of PI3-K signaling. Knockout mice display progressive replacement of the acinar pancreas with highly proliferative ductal structures that contain abundant mucins and express Pdx1 and Hes1, two markers of pancreatic progenitor cells. Moreover, a fraction of these mice develop ductal malignancy. We provide evidence that ductal metaplasia results from the expansion of centroacinar cells rather than transdifferentiation of acinar cells. These results indicate that Pten actively maintains the balance between different cell types in the adult pancreas and that misregulation of the PI3-K pathway in centroacinar cells may contribute to the initiation of pancreatic carcinoma in vivo.

Original languageAmerican English
Pages (from-to)185-195
Number of pages11
JournalCancer Cell
Volume8
Issue number3
DOIs
StatePublished - Sep 2005

Bibliographical note

Funding Information:
We are grateful to O. Martinez and R. Datar for expert technical assistance; A. McMahon and C. Lobe for gifts of mice; M. Gannon, C. Swift, and R. MacDonald for gifts of DNA constructs; and C. Wright, T. Sudo, and O. Madsen for gifts of antibodies. We are grateful to S. Thayer for helpful discussions and for supplying the image in Figure S6A , to T. Nir for providing the image in Figure S6B , and to I. Ben-Porath and members of the Melton laboratory for useful suggestions. Supported by NIH KO8 DK064136 (B.Z.S.), JDRF (Y.D.), the Lustgarten Foundation and King Trust (N.B.), and the DOD (H.W. and B.S.). D.A.M. is a Howard Hughes Medical Institute investigator. R.A.D. is an American Cancer Society Research Professor and an Ellison Senior Foundation Scholar and is supported by an NCI MMHCC U01 grant.

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