Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse

Sunil R. Hingorani, Emanuel F. Petricoin, Anirban Maitra, Vinodh Rajapakse, Catrina King, Michael A. Jacobetz, Sally Ross, Thomas P. Conrads, Timothy D. Veenstra, Ben A. Hitt, Yoshiya Kawaguchi, Don Johann, Lance A. Liotta, Howard C. Crawford, Mary E. Putt, Tyler Jacks, Christopher V.E. Wright, Ralph H. Hruban, Andrew M. Lowy, David A. Tuveson

Research output: Contribution to journalArticle

Abstract

To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRASG12D to progenitor cells of the mouse pancreas. We find that physiological levels of KrasG12D induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.

Original languageEnglish (US)
Pages (from-to)437-450
Number of pages14
JournalCancer cell
Volume4
Issue number6
DOIs
StatePublished - Dec 2003

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., Kawaguchi, Y., Johann, D., Liotta, L. A., Crawford, H. C., Putt, M. E., Jacks, T., Wright, C. V. E., Hruban, R. H., Lowy, A. M., & Tuveson, D. A. (2003). Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer cell, 4(6), 437-450. https://doi.org/10.1016/S1535-6108(03)00309-X