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p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells

Oncogene volume 35, pages 42824288 (11 August 2016) | Download Citation

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Abstract

Pancreatic cancer is one of the most lethal malignancies, with virtually all patients eventually succumbing to their disease. Mutations in p53 have been documented in >50% of pancreatic cancers. Owing to the high incidence of p53 mutations in PanIN 3 lesions and pancreatic tumors, we interrogated the comparative ability of adult pancreatic acinar and ductal cells to respond to oncogenic Kras and mutant Tp53R172H using Hnf1b:CreERT2 and Mist1:CreERT2 mice. These studies involved co-activation of a membrane-tethered GFP lineage label, allowing for direct visualization and isolation of cells undergoing Kras and mutant p53 activation. Kras activation in Mist1+ adult acinar cells resulted in brisk PanIN formation, whereas no evidence of pancreatic neoplasia was observed for up to 6 months following Kras activation in Hnf1beta+ adult ductal cells. In contrast to the lack of response to oncogenic Kras alone, simultaneous activation of Kras and mutant p53 in adult ductal epithelium generated invasive PDAC in 75% of mice as early as 2.5 months after tamoxifen administration. These data demonstrate that pancreatic ductal cells, whereas exhibiting relative resistance to oncogenic Kras alone, can serve as an effective cell of origin for pancreatic ductal adenocarcinoma in the setting of gain-of-function mutations in p53.

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Acknowledgements

We acknowledge Anzer Habibulla, Danielle Blake, Mara Swaim, Jeffery Roeser and Qingfeng Zhu for their help in maintaining mouse colonies and genotyping. We thank Jorge Ferrer for providing the Hnf1b mice. This work was supported by NIH P01 CA134292 and R21 CA158898 (to SDL). JMB was supported by an NIH F32CA157044 and an AACR/Pancreatic Cancer Action Network Pathway to Leadership Award. NCJ was supported by an NIH T35 DK007676-22.

Author contributions

Conception and design, and writing the manuscript: JMB and SDL; acquisition of data: JMB, AMH, JA and AM; analysis and interpretation of data (statistical analysis, biostatistics and computational analysis): JMB, SDL, AMH, KJL, MY, CAI-D and AM; Administrative, technical or material support: JMB, AMH, MAP, NCJ.

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Affiliations

  1. Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX, USA

    • J M Bailey
    • , A M Hendley
    • , M A Pruski
    •  & N C Jones
  2. The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • K J Lafaro
    • , C A Iacobuzio-Donahue
    •  & S D Leach
  3. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • J Alsina
  4. Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA

    • M Younes
  5. Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • A Maitra
  6. Departments of Clinical Cancer Prevention and GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • F McAllister

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The authors declare no conflict of interest.

Corresponding author

Correspondence to J M Bailey.

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DOI

https://doi.org/10.1038/onc.2015.441

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

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