TY - JOUR
T1 - β-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice
AU - Morris IV, John P.
AU - Cano, David A.
AU - Sekine, Shigeki
AU - Wang, Sam C.
AU - Hebrok, Matthias
PY - 2010/2/1
Y1 - 2010/2/1
N2 - Cellular plasticity in adult organs is involved in both regeneration and carcinogenesis. WT mouse acinar cells rapidly regenerate following injury that mimics acute pancreatitis, a process characterized by transient reactivation of pathways involved in embryonic pancreatic development. In contrast, such injury promotes the development of pancreatic ductal adenocarcinoma (PDA) precursor lesions in mice expressing a constitutively active form of the GTPase, Kras, in the exocrine pancreas. The molecular environment that mediates acinar regeneration versus the development of PDA precursor lesions is poorly understood. Here, we used genetically engineered mice to demonstrate that mutant Kras promotes acinar-to-ductal metaplasia (ADM) and pancreatic cancer precursor lesion formation by blocking acinar regeneration following acute pancreatitis. Our results indicate that β-catenin is required for efficient acinar regeneration. In addition, canonical β-catenin signaling, a pathway known to regulate embryonic acinar development, is activated following acute pancreatitis. This regeneration-associated activation of β-catenin signaling was not observed during the initiation of Kras-induced acinar-to-ductal reprogramming. Furthermore, stabilized β-catenin signaling antagonized the ability of Kras to reprogram acini into PDA preneoplastic precursors. Therefore, these results suggest that β-catenin signaling is a critical determinant of acinar plasticity and that it is inhibited during Kras-induced fate decisions that specify PDA precursors, highlighting the importance of temporal regulation of embryonic signaling pathways in the development of neoplastic cell fates.
AB - Cellular plasticity in adult organs is involved in both regeneration and carcinogenesis. WT mouse acinar cells rapidly regenerate following injury that mimics acute pancreatitis, a process characterized by transient reactivation of pathways involved in embryonic pancreatic development. In contrast, such injury promotes the development of pancreatic ductal adenocarcinoma (PDA) precursor lesions in mice expressing a constitutively active form of the GTPase, Kras, in the exocrine pancreas. The molecular environment that mediates acinar regeneration versus the development of PDA precursor lesions is poorly understood. Here, we used genetically engineered mice to demonstrate that mutant Kras promotes acinar-to-ductal metaplasia (ADM) and pancreatic cancer precursor lesion formation by blocking acinar regeneration following acute pancreatitis. Our results indicate that β-catenin is required for efficient acinar regeneration. In addition, canonical β-catenin signaling, a pathway known to regulate embryonic acinar development, is activated following acute pancreatitis. This regeneration-associated activation of β-catenin signaling was not observed during the initiation of Kras-induced acinar-to-ductal reprogramming. Furthermore, stabilized β-catenin signaling antagonized the ability of Kras to reprogram acini into PDA preneoplastic precursors. Therefore, these results suggest that β-catenin signaling is a critical determinant of acinar plasticity and that it is inhibited during Kras-induced fate decisions that specify PDA precursors, highlighting the importance of temporal regulation of embryonic signaling pathways in the development of neoplastic cell fates.
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U2 - 10.1172/JCI40045
DO - 10.1172/JCI40045
M3 - Article
C2 - 20071774
AN - SCOPUS:76649105065
SN - 0021-9738
VL - 120
SP - 508
EP - 520
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -