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Oncogenic Ras/Src cooperativity in pancreatic neoplasia

Oncogene volume 30, pages 2123–2134 (2011)Cite this article

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Abstract

Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c-Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5–8 weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA's indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src-driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer.

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Acknowledgements

We thank Charles Yi and Dana Wu for excellent technical assistance. We acknowledge Richard Aspinall, Lisette Acevedo, Josh Greenberg and David Tuveson for valuable discussions, Greg Boivin for histological analysis, as well as Richard Levenson and Kristin Lane for NuBrio imaging. This work was supported by NIH grants R21CA104898, P01-CA078045 (DAC) and Collaborative Translational Research grants from Moores UCSD Cancer Center (DAC, DJS and AML).

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Authors and Affiliations

  1. Department of Pathology, Moore's UCSD Cancer Center, San Diego, CA, USA

    D J Shields, E A Murphy, J S Desgrosellier, A Mielgo, S K M Lau, L A Barnes, J Lesperance, M Huang, D Tarin & D A Cheresh

  2. Genomics Institute of Novartis Research Foundation, San Diego, CA, USA

    C Schmedt

  3. Department of Surgery, Moore's UCSD Cancer Center, San Diego, CA, USA

    A M Lowy

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  1. D J Shields
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Correspondence to D A Cheresh.

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Shields, D., Murphy, E., Desgrosellier, J. et al. Oncogenic Ras/Src cooperativity in pancreatic neoplasia. Oncogene 30, 2123–2134 (2011). https://doi.org/10.1038/onc.2010.589

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