Our research revolves around understanding how the Ras family of small GTPases impinges upon tumor invasion and metastasis, specifically in pancreatic ductal cancer.  Ras is a nodal point of signaling, with input and activation from a wide range of stimuli including receptor tyrosine kinases, G protein-coupled receptors, integrins and extracellular matrix interactions, and chemokines.  Once activated, Ras in turn triggers several signaling cascades that lead to a variety of transformed phenotypes including loss of cell cycle control, decreased cell death, and metastatic spread.  Of particular interest to my lab is delineating how Ras activation in epithelial tumor cells drives signaling crosstalk to other compartments of the tumor microenvironment including stromal fibroblasts, macrophages, and vascular components.  Paracrine signaling among these disparate cell populations likely contributes to protection of epithelial cells from cell cycle arrest, apoptosis, and senescence, as well as facilitating dedifferentiation and EMT.

At the same time that crosstalk affects the epithelial cells, there is evidence that aberrant activation of Ras leads to changes in extracellular matrix (ECM).  Reorganization and dissolution of ECM by proteases and other enzymes accelerates cell migration for locoregional invasion and distal metastasis.  In addition to Ras effects on the ECM architecture, we have recently shown that activation of this family of GTPases in pancreatic cancer leads to expression and secretion of CXC chemokines that is in part MAP kinase dependent.  Vascular endothelial cells are sensitive to these chemokines via CXCR2 receptors, and respond by showing increased migration, invasion, and organization into vessel precursors.  This angiogenesis may provide not only a means to nourish nascent tumors, but also serve as a conduit for malignant spread. As a result, we are interested in testing the hypothesis that small molecule inhibitors of the CXC-CXCR signaling axis may reduce the invasion and metastasis of pancreatic cancer and/or the expansion of already disseminated micrometastases.

Pancreatic cancer is also characterized by having an extensive stromal component.  It is hypothesized that this bulk of fibroid tissue may be one of the reasons pancreatic cancer remains particularly insensitive to chemotherapeutic agents.  Another arm of our research attempts to investigate whether tumor fibroblasts, like vascular endothelial cells, are responsive to CXC-CXCR crosstalk signaling triggered initially by epithelial K-Ras activation.

It is well established that mutational activation of K-Ras occurs very early in pancreatic ductal dysplasia and remains an important signaling impetus through the development of malignancy.  We are investigating whether the signaling crosstalk between Ras and CXC chemokines is similarly triggered early in cancer progression by screening patient samples of initial dysplasia (pancreatic intraepithelial neoplasia, PanIN) to frank adenocarcinoma.  By understanding the progression this signaling, we hope to uncover biomarkers to be used for screening and earlier detection.