Journal
GENES & DEVELOPMENT
Volume 20, Issue 22, Pages 3161-3173Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1470806
Keywords
pancreatic cancer; hedgehog; Kras; mouse model
Categories
Funding
- NCI NIH HHS [R01 CA087837-07, P30 CA082103, CA87837, CA112537-01, R01 CA112537, R01 CA087837-02S1, R01 CA087837, P30 CA82103, P30 CA046592] Funding Source: Medline
- NIAMS NIH HHS [R01 AR045973, AR45973] Funding Source: Medline
- NIDDK NIH HHS [P30 DK63720, DK60533-01A1, P30 DK063720, R01 DK060533] Funding Source: Medline
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Pancreatic ductal adenocarcinoma (PDA) constitutes a lethal disease that affects > 30,000 people annually in the United States. Deregulation of Hedgehog signaling has been implicated in the pathogenesis of PDA. To gain insights into the role of the pathway during the distinct stages of pancreatic carcinogenesis, we established a mouse model in which Hedgehog signaling is activated specifically in the pancreatic epithelium. Transgenic mice survived to adulthood and developed undifferentiated carcinoma, indicating that epithelium-specific Hedgehog signaling is sufficient to drive pancreatic neoplasia but does not recapitulate human pancreatic carcinogenesis. In contrast, simultaneous activation of Ras and Hedgehog signaling caused extensive formation of pancreatic intraepithelial neoplasias, the earliest stages of human PDA tumorigenesis, and accelerated lethality. These results indicate the cooperation of Hedgehog and Ras signaling during the earliest stages of PDA formation. They also mark Hedgehog pathway components as relevant therapeutic targets for both early and advanced stages of pancreatic ductal neoplasia.
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