ECT2 Isoform Switch in Pancreatic Cancer.

PROJECT SUMMARY/ABSTRACT Epithelial Cell Transforming Sequence 2 (ECT2) is a guanine nucleotide exchange factor that activates the function of RHO family GTPases. ECT2 expression is induced and prognostic in pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancer types. Our goal is to define the role of ECT2 in PDAC transformation. Two major ECT2 mRNA variants (ECT2-Ex4+ and ECT2-Ex4-) have been shown to express in cells through alternative splicing events that include or exclude exon 4 of the ECT2 gene. Our preliminary data indicate that: 1) ECT2 expression is elevated in PDAC precancerous lesions and PDAC tumors; 2) the ratio of ECT2-Ex4+ to ECT2-Ex4- expressed is elevated in primary PDAC tumors and cell lines when compared to normal pancreas cells and tissues; 3) an elevated ECT2-Ex4+ to ECT2-Ex4- ratio correlates clinically to poorer survival rates in PDAC patients; and 4) ECT2 is required for PDAC cell transformation. We hypothesize that the ECT2-Ex4+ isoform is oncogenic in PDAC and may serve as a biomarker of PADC progression and novel therapeutic target. This hypothesis will be tested through completion of three interrelated specific aims designed to: 1) determine the status of ECT2-Ex4+ in PDAC precursor lesions and PDAC tumors in situ; 2) define the specific role of ECT2-Ex4+ in normal pancreas cells and PDAC tumor growth and metastasis; and 3) determine the role of ECT2 exon 4 on ECT2 oncogenic signaling in PDAC cells. Successful completion of these studies will provide new insight into the role of ECT2 in PDAC transformation and enhance our understanding of PDAC progression. In addition, our studies will facilitate the development of a novel biomarker for early PDAC diagnosis. Finally, our studies may reveal an ECT2 isoform switch as a novel therapeutic vulnerability in PDAC.