Defining the Role for A Lipid Kinase in the Progression of Pancreatic Cancer

Mayo Clinic Rochester, Rochester MN

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Abstract

DESCRIPTION (provided by applicant): As the fourth most common cause of cancer-related deaths in the US and the eighth worldwide, pancreatic cancer has an extremely poor prognosis with a <6% 5-year survival rate due to its aggressively metastasis. Although abnormally activated K-Ras and EGFR haven been clearly associated with the initiation and progression of pancreatic cancer, the downstream signaling molecules responding to these stimulation to drive the rapid progression of this malignancy are far from fully understood. This limits the development of efficient diagnostic and therapeutic strategies against this deadly disease. Our long-term goal is to understand the molecules and mechanisms that control the initiation and progression of pancreatic cancer. Toward this end, we start from dissecting the role of a specific lipid kinase, type I? phosphatidylinositol phosphate kinase (PIPKI?), in pancreatic cancer development. PIPKI? generates phosphatidylinositol-4,5-bisphosphate (PI4,5P2), which is not only the substrate of PI 3-Kinase, but also a critical lipid second messenger for cell migration and invasion by regulating actin reorganization, cell adhesion assembly, and vesicular trafficking. Our published and preliminary results suggest that PIPKI? is an important player downstream of receptor tyrosine kinases such as EGFR and c-Met in the formation of metastatic pancreatic cancer. In the proposed study, we will employ mouse models to test whether PIPKI? is necessary for the initiation and progression of pancreatic neoplasia spontaneously generated in these animals. To do so, we have generated mice with conditional deletion of PIPKI?i2 (PIPKI? isoform that can be phosphorylated by receptor tyrosine kinases) concomitant with K-RasG12D expression with or without p53 loss-of-function mutants in the pancreas. We will determine and compare the initiation and progression of acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia (PanIN), and aggressive pancreatic ductal carcinoma in control and PIPKI?-depleted pancreata obtained from these animals. In particular, we will determine whether PIPKI? is required for the initiation, maintenance, and/or differentiation of pancreatic tuft cells, the PanIN stem cells. Whether the receptor tyrosine kinase-mediated phosphorylation is critical for PIPKI? to promote cancer metastasis will also be tested by suppression/re-expression approach using orthotopical transplantation model. Results from these experiments will shed a light on the signaling pathway downstream of receptor tyrosine kinase and K-Ras in the development of pancreatic cancer. Ultimately, we hope to translate this knowledge into new strategies for detecting cells where PI4,5P2 signaling is not appropriately regulated, before they have the opportunity to develop into aggressive metastatic tumors. Furthermore, these studies will provide potent candidates for new biomarkers and cancer drug targets. The outcomes of this project will clearly benefit both basic research and clinical patient care.