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Published on: October 4, 2022
Hedgehog/Ras interactions regulate early stages of pancreatic cancer
Marina Pasca di Magliano1, Shigeki Sekine, Alexandre Ermilov
1Diabetes Center, Department of Medicine, University of California, San Francisco, California 94143, USA.
Abstract:
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.
Insights
Hedgehog signaling alone drives pancreatic cancer in mice, but combining it with Ras signaling creates early-stage tumors. This highlights Hedgehog and Ras pathway cooperation in pancreatic ductal adenocarcinoma development and suggests therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with over 30,000 annual US cases.
- Aberrant Hedgehog signaling is implicated in PDA pathogenesis.
- Understanding Hedgehog pathway roles in distinct carcinogenesis stages is crucial.
Purpose of the Study:
- To investigate the role of Hedgehog signaling in pancreatic carcinogenesis.
- To determine the impact of combined Hedgehog and Ras signaling activation in pancreatic cancer development.
Main Methods:
- Established a transgenic mouse model with epithelium-specific Hedgehog signaling activation.
- Analyzed tumor formation and survival in mice with activated Hedgehog signaling alone and in combination with Ras signaling.
Main Results:
- Epithelium-specific Hedgehog activation led to undifferentiated carcinoma but did not fully recapitulate human PDA.
- Simultaneous activation of Ras and Hedgehog signaling induced early-stage pancreatic intraepithelial neoplasias (the earliest PDA precursor lesions).
- Combined signaling accelerated lethality in the mouse model.
Conclusions:
- Hedgehog and Ras signaling cooperate during the initial stages of pancreatic ductal adenocarcinoma formation.
- Hedgehog pathway components represent potential therapeutic targets for both early and advanced PDA.
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