This R21 application (in response to PA-06-303, titled """"""""Pilot Studies in Pancreatic Cancer"""""""") is based on our recent finding that lysophosphatidic acid (LPA), a simple, bioactive glycerophospholipid that stimulates its cognate G protein coupled receptors (GPCRs) can activate both oncogenic cell growth and cell migration in addition to transactivating c-Met in pancreatic cancer cells. LPA, the ligand for a family of LPA-receptors (LPARs), has emerged as a factor of biological importance in the progression of ovarian as well as pancreatic cancers. Recent studies have shown that LPA can stimulate pancreatic cancer cell migration as well as the transactivation of c-Met, which is known to be critically involved in the motility of many cancer cell lines. However, relatively little is known about underlying mechanisms. In this context, our recent findings that the gep oncogene G mediated transactivation of receptor tyrosine kinases and cell movement are of great significance. Based on these findings, we hypothesize that a specific LPA-receptor stimulates the progression of pancreatic cancer via distinct heterotrimeric G proteins and the downstream small GTPases. This hypothesis will be tested under the following specific aims:
Aim -1. Define the LPA-receptor(s) involved in the transactivation of c-Met, migration, and invasion of pancreatic cancer cells. Using siRNA specific to each of these receptors, we will define the receptor that mediates the transactivation of c-Met and invasive migration of pancreatic cancer cell lines using a panel of cancer cell lines consisting of BcPC3, Dan G. MDAPanc-28, and Mia PaCa-2 cells.
Aim -2. Define the heterotrimeric G protein that couples LPARs to cellular responses involved in the transactivation of c-Met, migration, and invasion. LPARs have been shown to transmit their messages via the heterotrimeric G proteins defined by the G mutants of the respective LPAR (identified in the previous aim) to the intracellular effectors. In addition to characterizing novel etiological factors involved in the progression of pancreatic cancer, the outcome of these studies is expected to identify novel therapeutic targets for the treatment of the disease. These studies will identify and characterize novel etiological factors involved in the genesis and progression of pancreatic cancer. In addition, the outcome of these studies is expected to identify novel diagnostic, prognostic and therapeutic targets for pancreatic cancer. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA125752-02
Application #
7455333
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2007-06-26
Project End
2009-03-31
Budget Start
2008-06-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$118,057
Indirect Cost
Name
Temple University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Gardner, Jacob A; Ha, Ji Hee; Jayaraman, Muralidharan et al. (2013) The gep proto-oncogene G?13 mediates lysophosphatidic acid-mediated migration of pancreatic cancer cells. Pancreas 42:819-28