Integrated transcriptomic profiling reveals oncogenic pathways and chimeric transcripts in equine sarcoid lesions...

Sarcoids are the most common cutaneous tumors in horses, representing up to 90% (35%-90%) of skin neoplasms. Mostly caused by Bovine Papillomavirus (BPVs) infections, sarcoids are highly resistant to therapy and prone to recurring, posing a significant threat to equine health. The aim of this study is to explore molecular pathogenetic mechanisms underlying the development of equine sarcoids, by applying transcriptomic approach. After testing samples for viral DNA, both mRNA and small RNA expression was analyzed via high-throughput Illumina sequencing comparing 12 sarcoids and 12 healthy skin samples as controls. Differentially expressed genes (DEGs), DE miRNAs (sarcoids vs. controls) and miRNA-DEG couples with opposite expression trends, were retrieved and subjected to a functional analysis. Over 6K DEGs emerged, 3620 down-regulated and 2415 up-regulated along with 145 DE miRNAs, 56 downregulated and 89 upregulated. Among the enriched biological processes for DEGs, some were related to growth factors production and collagen binding, cell migration and proliferation, tissue morphogenesis and inflammatory response. Interestingly, "Pathways in cancer" and "Hippo signaling pathway" were enriched KEGG pathways for the miRNA-DEG couples. Our data identified a great transcription discrepancy between sarcoid lesions and healthy skin with an overall enrichment for processes related to cellular transformation. RNA-seq sequencing depth allowed the search for candidate chimeric transcripts associated with viral integration events. Chimeric RNAs can influence gene regulation and may contribute to tumor growth and immune modulation. Via computational analysis we identified six fusion loci in tumor samples and in two sarcoid margins, with the most frequent event involving WNT10B and FKBP11. This fusion, detected in 6/10 sarcoids, is of particular interest since WNT10B activates the WNT/β-catenin cascade, while FKBP11 has been implicated in osteosarcoma progression. Although functional validation is ongoing, this represents the first report of chimeric transcripts in equine sarcoids, opening new perspectives on BPV-driven oncogenesis.