Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and biologically aggressive malignancy that causes approximately 34,000 deaths in the United States each year. PDAC harbors several molecular alterations including activating KRAS mutations, homozygous deletion of the tumor suppressor gene p16INK4A/p14ARF, and overexpression of heparin binding growth factors and their receptors. In addition, glypican-1 (GPC1), a cell-surface heparan sulfate proteoglycan (HSPG) is released by cancer cells, expressed by fibroblasts, and is over-expressed in PDAC. GPC1 enhances the signaling pathways activated by several heparin binding growth factors (HBGFs), especially fibroblast growth factors (FGFs), heparin binding EGF like growth factor (HB-EGF), and heregulins. These HBGFs play critical roles in cell growth, differentiation, adhesion, transformation and metastasis. Additionally, suppression of GPC1 abrogates mitogenic signaling in response to HBGFs in vitro and attenuates tumor growth and metastasis in vivo. These data indicate that GPC1 is not only overexpressed in PDAC but also that host-derived and cancer cell-derived GPC1 contribute to enhanced tumor growth, angiogenesis, and metastasis. Therefore, three specific aims are proposed to test the hypothesis that GPC1 plays a pivotal role in PDAC progression and metastasis by enhancing oncogenic signaling pathways both in the tumor and within the tumor associated stroma. First, tumors and primary cancer cell lines isolated from the novel transgenic mouse model: Pdx-1-Cre;LSL-KrasG12D;INK4ALox/Lox;GPC1+/+ orGPCI -/-will be fully characterized through a series of mechanistic in-vitro assays desined to assess the impact of GPC1 on proliferation, migration, and invasion. Next, in order to delineate the structural components critical for GPC1 signaling functions, primary cancer cell lines that overexpress modified versions of GPC1 will be studied both in vitro and in an orthotopic syngeneic mouse model. Lastly, two transgenic mouse models will be created, one that overexpresses GPC1 alone and another that overexpresses GPC1 in conjunction with activated KrasG12D. These mouse models will be used to determine GPC1 contribution to the initiation and/or progression of pancreatic adenocarcinomas. This research will not only significantly enhance our understanding of how GPC1 functions, especially what regions are critical for its activity, but it will also assess the importance of GPC1 in tumor development and progression in pancreatic cancer. These data may provide support for the efficacy of targeting GPC1 either alone or in combination with other therapeutic targets.
|Whipple, C A; Young, A L; Korc, M (2012) A KrasG12D-driven genetic mouse model of pancreatic cancer requires glypican-1 for efficient proliferation and angiogenesis. Oncogene 31:2535-44|