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Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Oncogene volume 29, pages 674–686 (2010)Cite this article

Abstract

Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4–/– cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT–mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.

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Acknowledgements

We thank Dr Douglas Melton for providing Pdx-Cre mice; Dr Hong Wu for Pten conditional mutant mice; and members of the Deng lab for critically reading the paper. This research was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA.

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  1. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    X Xu, B Ehdaie & C -X Deng

  2. Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

    N Ohara & T Yoshino

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  1. X Xu
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  2. B Ehdaie
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  3. N Ohara
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Correspondence to C -X Deng.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Xu, X., Ehdaie, B., Ohara, N. et al. Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene 29, 674–686 (2010). https://doi.org/10.1038/onc.2009.375

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