Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia.
Primary cilia have been proposed to participate in the modulation of growth factor signaling pathways. In this study, we determined that ciliogenesis is suppressed in both pancreatic cancer cells and pancreatic intraepithelial neoplasia (PanIN) lesions in human pancreatic ductal adenocarcinoma (PDAC). Primary cilia were absent in these cells even when not actively proliferating. Cilia were also absent from mouse PanIN cells in three different mouse models of PDAC driven by an endogenous oncogenic Kras allele. Inhibition of Kras effector pathways restored ciliogenesis in a mouse pancreatic cancer cell line, raising the possibility that ciliogenesis may be actively repressed by oncogenic Kras. By contrast, normal duct, islet, and centroacinar cells retained primary cilia in both human and mouse pancreata. Thus, arrested ciliogenesis is a cardinal feature of PDAC and its precursor PanIN lesions, does not require ongoing proliferation, and could potentially be targeted pharmacologically.
Seeley
E Scott
ES
Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03756, USA.
Carrière
Catherine
C
Goetze
Tobias
T
Longnecker
Daniel S
DS
Korc
Murray
M
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D018385:Centrosome / Q000473:pathology; D002923:Cilia / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)