Ras-driven transformation of human nestin-positive pancreatic epithelial cells.
Mutational activation of the K-Ras oncogene is well established as a key genetic step in the development and growth of pancreatic adenocarcinomas. However, the means by which aberrant Ras signaling promotes uncontrolled pancreatic tumor cell growth remains to be fully elucidated. The recent use of primary human cells to study Ras-mediated oncogenesis provides important model cell systems to dissect this signaling biology. This chapter describes the establishment and characterization of telomerase-immortalized human pancreatic duct-derived cells to study mechanisms of Ras growth transformation. An important strength of this model system is the ability of mutationally activated K-Ras to cause potent growth transformation in vitro and in vivo. We have utilized this cell system to evaluate the antitumor activity of small molecule inhibitors of the Raf-MEK-ERK mitogen-activated protein kinase cascade. This model will be useful for genetic and pharmacologic dissection of the contribution of downstream effector signaling in Ras-dependent growth transformation.
Campbell
Paul M
PM
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Lee
Kwang M
KM
Ouellette
Michel M
MM
Kim
Hong Jin
HJ
Groehler
Angela L
AL
Khazak
Vladimir
V
Der
Channing J
CJ
D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D007381:Intermediate Filament Proteins / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000502:physiology*; D064231:Nestin; D010183:Pancreatic Ducts / Q000166:cytology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D018631:ras Proteins / Q000502:physiology*
D007381:Intermediate Filament Proteins; C117307:KRAS protein, human; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins