Transcriptomic landscape of transposable elements reveals - as a potential oncogene and therapeutic target in pancreatic adenocarcinoma.

Eukaryotic genomes contain numerous transposable elements (TEs), whose dysregulation threatens genome stability and may contribute to cancer. Pancreatic adenocarcinoma (PAAD) is among the deadliest cancers, marked by abundant stroma that obscures tumor-specific molecular signals, complicating bulk-tissue analyses. Here, using 71 patient-derived PAAD organoids, we show that TE activities may potentially promote tumorigenesis and provide a source of novel immunotherapeutic targets. We identify 16 new TE-derived transcripts fused with 15 known oncogenes, exhibiting potential oncogenic function and prognostic value. Notably, -, present in 29% of tumors, encodes a protein variant transcriptionally regulated by binding to the promoter. - isoform 2 is associated with increased cholesterol ester accumulation and lipid droplet formation mediated through coexpression, potentially fostering tumor progression. On the immunogenic front, HLA-I immunopeptidomics of AsPC-1 cells and DAC13 organoids identify over 11,000 peptides respectively. Althought mutation-derived neoantigens are rare, several peptides are originated from TE-chimeric transcripts, including four predicted by TEprof2. The peptide FLIQHLPLV, detected in 27% of organoids, exhibits robust immunogenicity, validated by T2 binding, mass spectrometry and ELISPOT assays with HLA-genotyped PBMCs. Together, these findings suggest that TE activities may contribute to PAAD progression and diversify its immunopeptidome, providing new opportunities for molecular subtyping and potential immunotherapeutic intervention.