Abstract B089: Identification of splicing factor U1A as a key regulator of aggressive subtypes in pancreatic cancer

Abstract Pancreatic cancer is a highly aggressive malignancy which is projected to become the second leading cause of cancer-related deaths by 2030. Emerging data identified subtypes of pancreatic cancer with distinct biology, with the squamous subtype showing the worst clinical outcome and resistance to treatment. Although previously thought to be rare, a considerable proportion of conventional pancreatic ductal adenocarcinoma (PDAC) in fact harbors squamous features and the basal subtype of pancreatic cancer, representing around 40% of PDAC, aligns closely with the molecular signature of the squamous subtype, which supports the observation that squamous features are prevalent in pancreatic tumors. However, all subtypes of pancreatic cancer are currently uniformly treated and subtype-specific treatments are yet to be developed. This highlights the need to identify key drivers of pancreatic tumors for the development of novel therapeutic strategies that are not only effective against classical PDAC, but also against more aggressive subtypes of pancreatic cancer including basal/squamous tumors. To uncover novel dependencies of basal/squamous tumors, we mapped a unique transcriptomic landscape of basal/squamous tumors derived from a novel Myc-based model, comparing them to classical adenocarcinomas derived from Kras;Trp53;Ptf1a (KPf/fC) mice. Interestingly, we found that the basal/squamous tumors preferentially upregulated genes encoding splicing factors, notably SNRPA, which encodes the U1A protein. Functional studies demonstrated that U1A was required for sphere formation of mouse and human basal/squamous tumor cells as well as the growth of patient-derived samples in vitro and in vivo, suggesting that U1A is a critical regulator of basal/squamous tumors. Integrated eCLIP-seq and RNA-seq analyses in basal/squamous tumor cells identified a unique role of U1A as a direct regulator of immune factors involved in interferon/ cytokine signaling and antigen processing, many of which played an important role in the growth and maintenance of basal/squamous tumor cells. In addition, deletion of U1A had a dramatic impact on alternative splicing in squamous tumors; alternatively spliced genes were enriched in essential pathways including chromatin organization and cell cycle. Importantly, the integrated dataset identified a sodium-hydrogen ion transporter as a critical downstream regulator of U1A function, and its inhibition significantly impaired the growth of aggressive squamous tumors. Collectively, these data identify U1A and its downstream factors as critical dependencies of basal/squamous tumors and delineate the mechanisms by which it controls aggressive states in pancreatic cancer. Citation Format: Mari Nakamura, Jennfier Lee, Suvrajit Maji, Chaolin Zhang, Tannishtha Reya. Identification of splicing factor U1A as a key regulator of aggressive subtypes in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B089.