Inner and Outer Determinants of Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its pronounced cellular heterogeneity, therapy resistance, and metastatic propensity, traits driven by cancer stem cells (CSCs). Once thought to be a rare, static subpopulation, CSCs are now recognized as a dynamic, plastic cell state influenced by both intrinsic and extrinsic factors. In this review, we explore the “inner” (genetic, cellular, and metabolic) and “outer” (microenvironmental and macroenvironmental) determinants that govern CSC identity, emergence, and evolution in PDAC. We focus on how acinar and ductal cell plasticity, in combination with oncogenic mutations (e.g., KRAS, TP53), contribute to tumor initiation and CSC generation, how genomic instability further fuels CSC heterogeneity and adaptability, and we highlight how micro and macro TME properties, metabolism and external factors regulate CSC behavior afterwards. Altogether, CSCs exist at the nexus of genetic chaos and environmental cues. Understanding this complex interplay is key to developing therapies that not only eradicate CSCs but also prevent their reemergence. While still far from clinical application, disrupting CSC-supportive networks should be a research and clinical focus for improving outcomes for PDAC patients.