| Abstract [eng] |
Pancreatic ductal adenocarcinoma is the most prevalent and aggressive form of pancreatic cancer, accounting for over 90% of cases. It is associated with poor prognosis, with a five-year survival rate below 10%, largely due to late-stage diagnosis, a highly desmoplastic tumor microenvironment, and resistance to standard therapies such as chemotherapy and radiotherapy. The molecular pathogenesis of pancreatic ductal adenocarcinoma is driven by genetic alterations, most notably KRAS mutations, which are present in over 90% of cases, along with TP53, SMAD4, and CDKN2A mutations that contribute to tumor progression, genomic instability, and resistance to therapy. The disease progresses from precursor lesions, such as pancreatic intraepithelial neoplasia (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms (MCNs), through the accumulation of sequential genetic mutations leading to invasive carcinoma. The latest scientific literature presents various classification schemes for pancreatic ductal adenocarcinoma subtypes. Some researchers distinguish between classical, squamous, immunogenic, and aberrantly differentiated subtypes, each characterized by distinct transcriptional profiles and clinical implications. However, many studies adopt a more simplified molecular classification approach, often categorizing pancreatic ductal adenocarcinoma into two primary subtypes—classical and basal—based on key molecular characteristics. Despite extensive research, conventional preclinical models, including two-dimensional (2D) cell cultures, genetically engineered mouse models, and patient-derived xenografts, exhibit significant limitations in recapitulating the genetic heterogeneity, stromal interactions, and therapeutic responses observed in pancreatic ductal adenocarcinoma patients. In contrast, organoid models have emerged as a promising platform for studying pancreatic ductal adenocarcinoma biology and treatment response. These three-dimensional (3D) structures, derived from patient tumors, retain the genetic, molecular, and phenotypic characteristics of the original malignancy, allowing for a more accurate representation of tumor heterogeneity. Pancreatic ductal adenocarcinoma organoids can be generated from surgical resections, fine-needle aspiration biopsies (EUS-FNB), and metastatic lesions. These models have demonstrated high fidelity in preserving tumor-specific molecular subtypes and can be used for personalized drug screening and pharmacotyping. Recent advancements in organoid technology, including the incorporation of stromal components such as cancer-associated fibroblasts (CAFs) and immune cells, have improved their ability to replicate the tumor microenvironment. Additionally, innovative methodologies such as 3D bioprinting and microfluidic systems enhance the reproducibility and scalability of these models, facilitating their integration into high-throughput drug screening platforms. Circulating tumor cell (CTC)-derived organoids represent a novel avenue for studying pancreatic ductal adenocarcinoma metastasis and therapeutic resistance, though further validation is required for their clinical implementation. Despite challenges related to culture standardization, tumor heterogeneity, and microenvironmental complexity, patient-derived organoid models constitute a promising research platform for biomarker discovery, individualized treatment optimization, the development of novel targeted therapies, and the refinement of standard clinical therapeutic approaches, ultimately contributing to improved quality of life and enhanced survival prognosis for patients with pancreatic ductal adenocarcinoma. |
