This project employs patient-derived pancreatic ductal adenocarcinoma (PDAC) organoids to investigate cancer stem cell (CSC) plasticity and exosome-mediated tumor-stroma/immune communication driving therapy resistance. Doctoral researchers will establish PDO biobank lines from primary and metastatic PDAC tissues, engineer advanced assembloids incorporating CAFs, TAMs, and endothelial cells within 3D bioprinted or organ-on-chip platforms, and perform longitudinal co-culture experiments tracking CSC marker dynamics (CD133, ALDH1, SOX2) under chemotherapy/radiotherapy pressure. Single-cell multiomics (scRNA-seq, spatial proteomics), extracellular vesicle (sEV) isolation and cargo profiling (miRNA, proteins), and high-throughput functional screens will map bidirectional communication networks, plasticity states enabling dormancy/expansion, and CSC-TME feedback loops. CRISPR-based perturbation of key exosomal regulators combined with patient-correlated validation identifies therapeutic vulnerabilities, aiming to develop stroma-reprogramming and CSC-depleting combination strategies to overcome PDAC treatment resistance.