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Mol. Cell. Biol. doi:10.1128/MCB.01621-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Pancreatic Lkb1 deletion leads to acinar polarity defects and cystic neoplasms

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Massachusetts General Hospital Cancer Center and Department of Medicine Harvard Medical, School, Boston MA, USA; Department of Cellular Biochemistry and Human Genetics, The Hebrew University–Hadassah, Medical School, Jerusalem, Israel; Department of Pathology Brigham and Woman's Hospital, Boston MA, USA; Center for Applied Cancer Science, Belfer Foundation Institute for Innovative Cancer Science; Department of Medicine and Genetics, Harvard Medical School, Boston, MA, USA

^* To whom correspondence should be addressed. Email: nelbardeesy{at}partners.org. ron_depinho{at}dfci.harvard.edu.

	Abstract

LKB1 is a key regulator of energy homeostasis through activation of AMPK and is functionally linked to vascular development, cell polarity and tumor suppression. In humans, germline LKB1 loss-of-function mutations causes Peutz-Jeghers syndrome (PJS) which is characterized by predisposition to gastrointestinal neoplasms marked by a high risk of pancreas cancer. Here, to explore the developmental and physiological functions of Lkb1 in vivo, we examined the impact of conditional Lkb1 deletion in the pancreas epithelium of the mouse. The Lkb1 deficient pancreas, although grossly normal at birth, demonstrates defective acinar cell polarity, abnormal cytoskeletal organization, loss of tight junctions, and inactivation of AMPK/MARK/SAD family kinases. Rapid and progressive postnatal acinar cell degeneration and acinar-to-ductal metaplasia occurs culminating in marked pancreatic insufficiency and in the development of pancreatic serous cystadenomas, a tumor type associated with PJS. Lkb1 deficiency also impacts on the pancreas endocrine compartment characterized by smaller and scattered islets and transient alterations in glucose control. These genetic studies provide in vivo evidence of a key role for LKB1 in the establishment of epithelial cell polarity that is vital for pancreatic acinar cell function and viability and the suppression of neoplasia.

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