Pancreatic cancer is a devastating disease with an exceptionally poor prognosis. Tumors of ductular origin comprise 95% of pancreatic neoplasms, have a strong tendency to invade into surrounding parenchyma, and metastasize to distal organs. Currently, the molecular mechanisms that support these critical processes are poorly defined. It is known that the actin cytoskeleton plays an important role and responds dynamically to stimulation by the epidermal growth factor receptor (EGF-R), which is significantly upregulated in many pancreatic tumors. This is a proposal to study the mechanisms by which reorganization of the actin cytoskeleton mediates loss of pancreatic ductular integrity and cell polarity leading to activation of cell migration, invasion, and metastasis. We have identified a key regulatory cytoskeletal complex in these cells comprised of a large mechanochemical GTPase called dynamin (Dyn2), the actin crosslinking protein cortactin, and the transforming kinase c-Src that is activated by the EGF-R and binds and phosphorylates both Dyn2 and cortactin. This is a resubmitted proposal that received a favorable first review. In response, we have conducted many new experiments to address the reviewers' helpful suggestions. These new data, and that presented in the original proposal, support the CENTRAL HYPOTHESIS of this study that the Dyn2-cortactin-c-Src complex is activated by EGF stimulation to mediate actin-plasma membrane dynamics in pancreatic ductular cells that promote invasion and metastasis. This proposal will test the participation of this protein complex toward the neoplastic process in 3 different human pancreatic tumor cell lines in vitro, using biochemical and microscopic approaches, and in vivo, via injection into nude mice. We will test the Hypotheses that: 1. The Dyn2-cortactin-c-Src complex mediates the EGF-stimulated disassembly of pancreatic ductular cell-cell-adherens junctions before metastasis. 2. This complex in pancreatic ductular cells is activated by the EGF-R to mediate the formation of unique dorsal """"""""wave"""""""" structures that specifically sequester receptor and ligand while reorganizing the actin cytoskeleton. 3. EGF stimulation of pancreatic ductular tumor cells activates the Dyn2-cortactin-c-Src complex leading to actin membrane reorganization, lamellipod extension, migration, and metastasis. This study will provide novel information toward understanding the molecular mechanisms that make pancreatic tumors aggressive, migratory, and lethal.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104125-03
Application #
7100219
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Ault, Grace S
Project Start
2004-08-01
Project End
2009-05-31
Budget Start
2006-07-31
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$265,742
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Razidlo, Gina L; Burton, Kevin M; McNiven, Mark A (2018) Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem 293:11143-11153
Zhu, Shizhen; Zhang, Xiaoling; Weichert-Leahey, Nina et al. (2017) LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis. Cancer Cell 32:310-323.e5
Boddicker, Rebecca L; Razidlo, Gina L; Feldman, Andrew L (2016) Genetic alterations affecting GTPases and T-cell receptor signaling in peripheral T-cell lymphomas. Small GTPases :1-7
Boddicker, Rebecca L; Razidlo, Gina L; Dasari, Surendra et al. (2016) Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma. Blood 128:1234-45
Cao, Hong; Eppinga, Robbin D; Razidlo, Gina L et al. (2016) Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process. Oncogene 35:1099-1110
Razidlo, Gina L; Magnine, Christopher; Sletten, Arthur C et al. (2015) Targeting Pancreatic Cancer Metastasis by Inhibition of Vav1, a Driver of Tumor Cell Invasion. Cancer Res 75:2907-15
Razidlo, Gina L; Schroeder, Barbara; Chen, Jing et al. (2014) Vav1 as a central regulator of invadopodia assembly. Curr Biol 24:86-93
Razidlo, Gina L; Wang, Yu; Chen, Jing et al. (2013) Dynamin 2 potentiates invasive migration of pancreatic tumor cells through stabilization of the Rac1 GEF Vav1. Dev Cell 24:573-85
McNiven, Mark A (2013) Breaking away: matrix remodeling from the leading edge. Trends Cell Biol 23:16-21
Feng, H; Liu, K W; Guo, P et al. (2012) Dynamin 2 mediates PDGFR?-SHP-2-promoted glioblastoma growth and invasion. Oncogene 31:2691-702

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