Pancreatic adenocarcinoma is currently the fourth leadingcause of cancer deaths in the United States. The 5-year survival rate ranges from 1% to 3%, and the median survival duration after diagnosis is less than 6 months. Pancreatic cancer is characterized by locally advanced or metastatic disease. However, the mechanisms by which it metastasizesare not known. To search for candidate genes overexpressed in metastatic pancreatic cancer, we previously analyzed differential gene expression in the highly liver-metastatic pancreatic cancer cellline Colo357L3.6pl and its nonmetastatic parental cell line, Colo357FG, using cDNA microarray and identified overexpression of the tropomyosin-related kinase B (TrkB) protein in Colo357L3.6pl cells. Although TrkB overexpression was significantly correlated with the development of livermetastasis, its function in pancreatic cancer metastasis remains unknown. In the present study, we demonstrated that overexpressed TrkB is an unglycosylated protein (~60 kDa) from an alternatively spliced transcript variant of TrkB (TrkB-T1) with a unique C-terminal 12-amino-acid sequence and is localized in the cytoplasm. Overexpression of Flag-tagged TrkB-T1 but not a Flag-tagged TrkB-T1 C-terminal deletion mutant (Flag-TrkB-T1\#916;C) in Colo357FG cells enhanced cell proliferation, promoted formation of colonies in soft agar, stimulate tumor cell invasion, and induced liver metastasis in an orthotopic xenograft mouse model of pancreatic cancer. TrkB-T1 interacted with Rho GDP dissociation inhibitor (GDI) in vivo, but Flag-TrkB-T1\#916;C did not. Furthermore, overexpression of Flag-TrkB-T1 and knockdown of GDI expression by a specific GDI short hairpin RNA promoted RhoA activation, but Flag-TrkB-T1\#916;C overexpression did not. Therefore, we demonstrated that TrkB-T1 overexpression induces liver metastasis of pancreatic cancer and uncovered a unique signaling mechanism by which TrkB-T1 sequesters GDI and activates RhoA.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4806.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO