Beyond the genome: alternative splicing as a key driver of cellular plasticity and clinical heterogeneity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with an exceptionally poor prognosis, characterized by a relatively stable and recurrent spectrum of driver mutations that fail to fully explain the clinical heterogeneity of the disease. In this review, we evaluate alternative splicing (AS) as an additional regulatory layer underlying tumor plasticity and adaptive rewiring. We provide a mechanistically integrated overview of AS dysregulation in PDAC, including the contributions of specialized bioinformatics resources and databases such as TCGASpliceSeq, OncoSplicing, and MAJIQlopedia. We discuss how dysregulation of splicing factors, particularly from the SR and hnRNP protein families, acts as an upstream regulator reprogramming the isoform landscape. Furthermore, we examine how AS deregulation functionally contributes to key hallmarks of malignancy, including apoptosis resistance, metabolic adaptation, and metastatic plasticity. Then, we critically address the methodological aspects of isoform identification and outline future research directions, emphasizing the need for protein-level validation and the translational potential of therapeutic strategies, such as antisense oligonucleotides or spliceosome inhibitors. In conclusion, this review establishes that AS represents a biologically important and potentially therapeutically exploitable dimension of PDAC molecular biology, extending classical genetic models of tumor pathogenesis. Role of alternative splicing in the acquisition of cancer hallmarks in pancreatic cancer. Alternative splicing increases transcript and protein diversity and modulates key cellular processes. In PDAC, its dysregulation increases cancer cell plasticity, promoting tumor growth and dissemination, metabolic adaptation to the desmoplastic microenvironment, and evasion of apoptosis.