Abstract C093: Dysregulated spliceosomal components promote pancreatic cancer progression

Abstract

Abstract Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatic ductal adenocarcinoma (PDAC) is not well understood. We found that two proteins involved in different stages of spliceosome assembly contribute to PDAC tumorigenesis by regulating alternative splicing, either through direct or indirect interaction with RNA. First, we showed that the splicing factor SRSF1—an RNA-binding protein involved in early spliceosome assembly—can induce pancreatitis and accelerate KRASG12D-mediated PDAC by activating the MAPK pathway. Moreover, the expression of SRSF1 decreased in morphologically normal pancreatic cells expressing KRASG12D to maintain cellular homeostasis. Second, we found that breast cancer amplified sequence 2 (BCAS2, also known as SPF27)—a spliceosome scaffold protein associated with conformational changes—also contributes to PDAC progression. Although BCAS2 does not bind RNA directly, it can regulate alternative splicing events in a sequence-specific manner by promoting the usage of specific 5’ splice sites. BCAS2 promotes the inclusion of exon 21, which has a weak 5' splice site, in the SOS Ras/Rac Guanine Nucleotide Exchange Factor 1 (SOS1) pre-mRNA, resulting in a more oncogenic isoform. These studies not only improve our understanding of the oncogenic role of aberrant alternative splicing, but also provide insights into the mechanisms of alternative-splicing regulation at different stages of spliceosome assembly. Citation Format: Ledong Wan, Kuan-Ting Lin, Mohammad A. Rahman, Yuma Ishigami, Alexander J. Kral, Dillon Voss, Zhikai Wang, Mads A. Jensen, John E. Wilkinson, Youngkyu Park, David A. Tuveson, Adrian R. Krainer. Dysregulated spliceosomal components promote pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C093.