Aptamer‐Targeted PrPC Drives Colorectal Cancer Metastasis via a LYN‐STAT3 Complex and Enables Liquid Biopsy Detection

Colorectal cancer (CRC) poses a significant global health challenge, highlighting the need for better diagnostic tools and molecular targets. Compared to traditional antibodies, aptamers, which are single-stranded oligonucleotides with high affinity and low immunogenicity, offer an ideal platform for discovering novel biomarkers. Based on this approach, we used the Cell-SELEX strategy to develop a high-affinity aptamer-based probe, WHY-3E, which successfully identified the cellular prion protein (PrPC) as a key molecular target. We observed that PrPC was significantly upregulated in CRC tissues, strongly correlating with unfavorable clinical outcomes. Functionally, PrPC promotes malignant phenotypes, including migration and invasion, by regulating MSN. Mechanistically, we revealed that PrPC physically translocates from the cell surface to the cytoplasm via endocytosis. Once internalized, it interacts with the STAT3-NTD and LYN-SH domains, facilitating the ternary complex formation that enhances LYN-mediated STAT3 phosphorylation, ultimately increasing MSN transcriptional activity. Moreover, the deubiquitinase USP18 stabilizes PrPC by removing its Lys48-linked ubiquitin chains, ensuring the continuous activation of this oncogenic axis. Notably, the WHY-3E aptamer achieved 90.6% sensitivity and 89.0% specificity in detecting PrPC-positive circulating exosomes in patient cohorts. These findings deepen the mechanistic understanding of CRC progression and offer novel strategic avenues for PrPC-targeted aptamer applications in non-invasive diagnostics.