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Oncogenic Ras/Src cooperativity in pancreatic neoplasia
D J Shields1, E A Murphy, J S Desgrosellier
1Department of Pathology, Moore's UCSD Cancer Center, San Diego, CA, USA.
Oncogene
|January 19, 2011
Summary
Activating Kras and Src signaling cooperate to accelerate pancreatic ductal adenocarcinoma (PDA) development. Inhibiting Src suppresses tumor growth, suggesting Src-directed therapies for pancreatic cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Pancreatic cancer is highly lethal, with Kras mutations in 95% of cases.
- Elevated c-Src activity is observed in over 60% of pancreatic cancers and linked to poor prognosis.
- The role of c-Src in Kras-driven pancreatic tumorigenesis is not fully understood.
Purpose of the Study:
- To investigate the contribution of c-Src activity to Kras-dependent pancreatic ductal adenocarcinoma (PDA) development.
- To determine if oncogenic Kras and c-Src signaling cooperate in PDA initiation and progression.
- To evaluate the therapeutic potential of Src inhibition in Kras/Src-driven pancreatic tumors.
Main Methods:
- Utilized genetic manipulation in mouse models to delete C-terminal Src kinase (CSK) in the context of oncogenic Kras.
- Analyzed tumor development, latency, and invasiveness.
- Established and analyzed cell lines derived from Ras/Src-induced PDA to assess signaling dependencies.
Main Results:
- Deletion of CSK alongside oncogenic Kras accelerated invasive PDA development within 5-8 weeks.
- CSK deletion alone did not induce neoplasia, and oncogenic Kras alone resulted in PDA with low frequency and long latency.
- Ras/Src-driven PDA cells demonstrated dependence on Src signaling, with Src inhibition suppressing tumor growth.
Conclusions:
- Oncogenic Kras and c-Src signaling cooperate to accelerate pancreatic ductal adenocarcinoma onset.
- Src inhibition represents a potential therapeutic strategy for pancreatic cancers driven by Ras/Src cooperativity.
- These findings highlight the critical role of Src in Kras-driven pancreatic tumorigenesis.
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