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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



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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  1. 1.

    , , , , , et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518: 495–501.

  2. 2.

    , , , , , et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 2012; 22: 737–750.

  3. 3.

    , , , , , et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc Natl Acad Sci USA 2008; 105: 18913–18918.

  4. 4.

    , , , , , et al. Ras activity levels control the development of pancreatic diseases. Gastroenterology 2009; 137: 82 e1–82 e6.

  5. 5.

    , , , , , et al. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat Cell Biol 2014; 16: 255–267.

  6. 6.

    , , , , , et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007; 11: 291–302.

  7. 7.

    , , , , , et al. DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 2014; 146: 245–256.

  8. 8.

    , , , , , et al. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell 2009; 17: 849–860.

  9. 9.

    , , , , , et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 2007; 133: 1999–2009.

  10. 10.

    , , , , , et al. A central role for RAF—>MEK—>ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov 2012; 2: 685–693.

  11. 11.

    , , , , , et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene 2014; 33: 532–535.

  12. 12.

    , . Ras activity in acinar cells links chronic pancreatitis and pancreatic cancer. Clin Gastroenterol 2009; 7(11 Suppl): S40–S43.

  13. 13.

    , , , , , et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci USA 2010; 107: 246–251.

  14. 14.

    , , , , , et al. Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell 2013; 23: 634–646.

  15. 15.

    , . Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1. J Biol Chem 2000; 275: 18794–18800.

  16. 16.

    , , , , , et al. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling. Cell 2014; 157: 382–394.

  17. 17.

    , , , , , et al. DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 146: 245–256.

  18. 18.

    , , , , , et al. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 2008; 134: 544–555.

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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.

Author information


  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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