The Spliceosome Scaffold Component BCAS2 Promotes Pancreatic Cancer Progression through Weak 5′ Splice Site–Dependent Splicing Regulation

Wan, Ledong, Wang, Mei, Ishigami, Yuma, Kral, Alexander J, Lin, Kuan-Ting, Merrill, Joseph R, Lyons, Scott K, Krainer, Adrian R (October 2026) The Spliceosome Scaffold Component BCAS2 Promotes Pancreatic Cancer Progression through Weak 5′ Splice Site–Dependent Splicing Regulation. bioRxiv. ISSN 2692-8205 (Submitted)

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. Dysregulated RNA splicing has emerged as a critical mechanism contributing to PDAC progression. However, whether structural components of the spliceosome regulate oncogenic alternative splicing was not known. Here, we identify the nineteen complex (NTC) component BCAS2/SPF27 as a critical regulator of PDAC progression. Elevated expression of BCAS2 in PDAC is associated with poor patient outcomes. Transcriptomic analyses revealed that BCAS2 specifically regulates alternative exons with weak splice sites. In particular, BCAS2 promotes SOS1 exon 21 inclusion and consequently RAC-signaling activation. Furthermore, splice-switching antisense oligonucleotide (ASO)-mediated skipping of SOS1 exon 21 suppressed PDAC proliferation and migration. Our findings uncover a role of BCAS2 in the regulation of weak splice-site usage and identify the BCAS2–SOS1–RAC signaling axis as a potential therapeutic vulnerability in pancreatic cancer.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
diseases & disorders > cancer > cancer types > pancreatic cancer
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL labs > Lyons lab
CSHL Post Doctoral Fellows
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 7 October 2026
Date Deposited: 23 Oct 2026 16:47
Last Modified: 23 Oct 2026 16:47
Related URLs:
URI: https://repository.cshl.edu/id/eprint/42346

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