Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies owing to late diagnosis, extensive intratumoral heterogeneity, a dense desmoplastic tumor microenvironment, and limited therapeutic responsiveness. Although current treatment regimens, including FOLFIRINOX and gemcitabine plus nab-paclitaxel, have modestly improved survival, chemoresistance and the lack of reliable predictive biomarkers continue to hinder precision oncology. Conventional two-dimensional cell lines and many in vivo models do not fully recapitulate the complex architecture, cellular interactions, and biological heterogeneity of human PDAC. Patient-derived organoids (PDOs) have emerged as physiologically relevant three-dimensional models that preserve the genetic, molecular, and phenotypic characteristics of the original tumor while enabling rapid ex vivo pharmacotyping and functional therapeutic evaluation. This review summarizes recent advances in PDAC organoid technology, including tissue acquisition, organoid establishment, molecular characterization, biobanking, and integration with cancer-associated fibroblasts, immune cells, endothelial cells, CRISPR/Cas9 genome editing, assembloid systems, and microfluidic organ-on-chip platforms. We further discuss the applications of PDOs in drug screening, molecular subtype characterization, modeling therapeutic resistance, and supporting precision treatment strategies, together with emerging evidence from prospective clinical studies. Finally, we critically examine the remaining translational challenges, including culture-induced phenotypic drift, limited microenvironmental complexity, interlaboratory variability, assay standardization, and regulatory implementation. Although PDOs represent promising platforms for functional precision oncology, widespread clinical adoption will require standardized methodologies, prospective multicenter validation, and regulatory qualification before routine integration into clinical decision-making.
Hee-Seung Lee, B. Koo· Cancer Biome and Targeted Th...· 0 citations
Plant receptor kinases perceive diverse peptide signals to coordinate stress responses and developmental programs. The HAESA-LIKE 3 (HSL3/NUT) receptor recognizes CTNIP/SCREW phytocytokines-disulfide-constrained peptides that regulate immune signaling and stress adaptation. However, how HSL3 distinguishes these structurally constrained peptides from linear signaling molecules remains unknown. Here we report near-atomic resolution cryo-EM structures of HSL3 in apo and CTNIP448-70-bound states at ∼2.6 Å, using Arabidopsis CTNIP4 as a representative family member, revealing the mechanism of disulfide-constrained peptide recognition. The conserved CTNIP motif occupies a negatively charged pocket in the C-terminal region of HSL3 through a combination of polar contacts, hydrogen bonds, salt bridges, and van der Waals interactions. The receptor employs a two-step recognition mechanism-electrostatic steering followed by motif anchoring-that enables rapid ligand capture, consistent with the dynamic nature of stress signaling. Notably, an N-glycan at Asn449 directly contacts the CTNIP4 peptide, establishing glycosylation as an active participant in ligand recognition. Structure-guided mutagenesis combined with reactive oxygen species (ROS) burst assays confirmed the functional importance of key binding interfaces. N-terminal truncation experiments revealed a minimal active fragment: CTNIP451-70 supported both rapid ROS production and sustained seedling growth inhibition, whereas the shorter CTNIP454-70 variant retained ROS activity but failed to trigger long-term seedling growth inhibition. Structure-guided coevolutionary analysis across plant lineages reveals patterns of both conserved and variable receptor-ligand interfaces, highlighting evolutionary flexibility while preserving core features of recognition. These conserved recognition principles, mediated by receptor glycosylation and evolutionary plasticity, enable specificity in peptide signaling, with implications for engineering stress-resilient crops.
