Alternative polyadenylation as a driver of pancreatic cancer

Dr. Michael Feigin
Roswell Park Comprehensive Cancer Center
Wednesday, March 20, 2019 - 11:00am
Pharmacy Building Room 850
While mutations are of clear importance to cancer pathogenesis, cancer can also be driven by alterations in gene expression. These expression variations occur though several mechanisms, including changes in DNA methylation, chromosomal alterations, or noncoding mutations in promoters and enhancers. We have demonstrated that somatic mutations within regulatory regions alter the expression of cancer drivers, regulate oncogenic pathways and provide prognostic information. However, our understanding of the regulatory processes driving tumorigenesis is far from complete. Tumors can co-opt the mRNA processing machinery to dysregulate the expression of oncogenes and tumor suppressors. One such dysregulated process, alternative polyadenylation (APA), is responsible for regulating 3’-untranslated region (UTR) length and is driven by a core set of factors that recognize sequences within the 3’-UTR before pre-mRNA cleavage and addition of the poly(A) tail. The 3’-UTR contains regulatory sequences, including miRNA and RNA binding protein binding sites, that control mRNA stability, function and subcellular localization. Therefore, altering the length of a 3’-UTR can have dramatic impacts on gene function and cellular phenotype. APA factor expression is altered in a variety of cancer types, resulting in alterations in gene expression. As several APA factors are enzymes, targeting this process may represent a novel cancer therapeutic approach. Pan-cancer analyses have revealed that hundreds of transcripts undergo APA; how these changes in 3’-UTR length are mechanistically linked to changes in gene expression and function are complex and only now being functionally addressed. The role of APA in pancreatic ductal adenocarcinoma (PDA) has been largely unaddressed. An understanding of the gene regulatory mechanisms driving PDA progression may provide novel targets for therapeutic intervention. We have begun to address this problem through an analysis of differential APA events in normal pancreas and PDA tumors, and observed widespread 3’-UTR shortening in PDA, correlating with expression changes in known PDA drivers and alterations in cancer signaling networks.
Dr. Stephane Angers
Centre for Pharmaceutical Oncology