Tumor-derived CDHR2-enriched extracellular vesicles engage ANPEP on liver sinusoidal endothelial cells to facilitate...

Liver metastasis is the leading cause of death in pancreatic ductal adenocarcinoma (PDAC), yet its molecular drivers remain poorly defined. Through integrated transcriptomic and proteomic screening of clinical specimens, we identify the membrane protein Cadherin-Related Family Member 2 (CDHR2) as a key orchestrator of hepatic colonization in PDAC. CDHR2 was upregulated in primary tumors versus adjacent tissues, further elevated in liver metastasis versus matched primary tumors, and markedly enriched in patient-derived plasma extracellular vesicles (EVs), peaking in patients with liver metastasis. Knockdown of CDHR2 in human PDAC cells suppressed proliferation, migration, and invasion, and in orthotopic models attenuated primary tumor growth, remodeled the tumor microenvironment, and reduced liver metastatic burden. Mechanistically, CDHR2 associated with PDK1 and promoted activation of the PDK1-AKT (Thr308) axis to drive proliferation. In turn, AKT activity correlated with the packaging of CDHR2 into EVs, coupling intrinsic signaling to EV cargo loading. Tumor-derived, CDHR2-enriched EVs formed a complex with Aminopeptidase N (ANPEP) on liver sinusoidal endothelial cells (LSECs), disrupting endothelial junctions and enhancing tumor-cell adhesion to enable transendothelial migration. Consistently, ANPEP inhibition or liver-specific knockdown curtailed hepatic colonization, whereas priming with CDHR2⁺ EVs accelerated it. Finally, systemic delivery of EV-encapsulated siCDHR2 suppressed established primary tumors and markedly reduced liver metastasis. Collectively, our findings define a tumor-intrinsic CDHR2-PDK1-AKT (Thr308) axis coupled to an exosomal CDHR2-ANPEP endothelial-priming program and provide proof-of-concept for exosomal siCDHR2 as a candidate strategy against PDAC liver metastasis.