Oncogenic Kras-Induced GM-CSF Production Promotes the Development of Pancreatic Neoplasia

• Published in: Cancer cell Vol. 21; no. 6; pp. 836 - 847
• Main Authors: Pylayeva-Gupta, Yuliya, Lee, Kyoung Eun, Hajdu, Cristina H., Miller, George, Bar-Sagi, Dafna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.06.2012
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; CD11b Antigen - metabolism; CD8-Positive T-Lymphocytes - metabolism; Cell Transformation, Neoplastic; Cells, Cultured; Epithelial Cells - metabolism; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HEK293 Cells; Humans; Immunoblotting; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Myeloid Cells - metabolism; Pancreatic Ducts - cytology; Pancreatic Ducts - metabolism; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Receptors, Chemokine - metabolism; RNA Interference
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2012.04.024

Stromal responses elicited by early stage neoplastic lesions can promote tumor growth. However, the molecular mechanisms that underlie the early recruitment of stromal cells to sites of neoplasia remain poorly understood. Here, we demonstrate an oncogenic KrasG12D-dependent upregulation of GM-CSF in mouse pancreatic ductal epithelial cells (PDECs). An enhanced GM-CSF production is also observed in human PanIN lesions. KrasG12D-dependent production of GM-CSF in vivo is required for the recruitment of Gr1+CD11b+ myeloid cells. The suppression of GM-CSF production inhibits the in vivo growth of KrasG12D-PDECs, and, consistent with the role of GM-CSF in Gr1+CD11b+ mobilization, this effect is mediated by CD8+ T cells. These results identify a pathway that links oncogenic activation to the evasion of antitumor immunity. ► Oncogenic KrasG12D upregulates the production of GM-CSF in pancreatic ductal cells ► GM-CSF is required for accumulation of Gr1+CD11b+ cells in neoplastic pancreata ► Gr1+CD11b+ cells counteract CD8+ T cell-mediated suppression of neoplastic growth ► KrasG12D-GM-CSF axis may promote pancreatic cancer by undermining antitumor immunity