Abstract
Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz–Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/β-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of β-catenin in the Pdx-1-Cre LKB1L/L β-cateninL/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of β-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the β-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/β-catenin signaling in PC harboring LKB1 deficiency.
Highlights
This article is an open access articlePancreatic cancer (PC) is the seventh leading cause of cancer death in both sexes worldwide [1,2]
Pathology analysis has revealed that PC appears to arise from three distinct precursor lesions that transform the pancreatic ducts: pancreatic intraepithelial neoplasms (PanINs), which are small and focal; intraductal papillary mucinous neoplasms (IPMNs), which are moderate-sized, papillary cystic lesions lined by mucin-producing tall columnar epithelium; and mucinous cystic neoplasms (MCNs), comprising oligomegacysts with a single thin layer of cuboidal and flattened epithelium and associated with an ovarian-type of stroma [9,10,11]
Liver kinase B1 (LKB1) Loss Specific to the Pancreas Leads to Severe Defects in Epithelial Cell Polarity and the Gradual Development of Mucin Cystadenoma of the Pancreas in Mice
Summary
This article is an open access articlePancreatic cancer (PC) is the seventh leading cause of cancer death in both sexes worldwide [1,2]. Pathology analysis has revealed that PC appears to arise from three distinct precursor lesions that transform the pancreatic ducts: pancreatic intraepithelial neoplasms (PanINs), which are small and focal; intraductal papillary mucinous neoplasms (IPMNs), which are moderate-sized, papillary cystic lesions lined by mucin-producing tall columnar epithelium; and mucinous cystic neoplasms (MCNs), comprising oligomegacysts with a single thin layer of cuboidal and flattened epithelium and associated with an ovarian-type of stroma [9,10,11] These lesions present distinct histological morphologies and clinical significance but share a common mutation profile. The basis of these structural and histological differences is unknown, but may be associated with the cell of origin, various mutation combinations, the order of the mutational events, or other factors [6]
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