Differential regulation of the proliferative and autophagic responses in murine and human pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) cells rely on autophagy to adapt to microenvironmental stress. In our recent work, we showed that baseline autophagy flux levels shape the proliferative capacity of human PDAC cells. Here, we extend these findings by demonstrating that low baseline autophagy is consistently associated with enhanced proliferation in vitro and in vivo across multiple human and murine PDAC models. While this inverse relationship between autophagy flux and proliferation is conserved across species, the underlying regulatory mechanisms diverge. Namely, changes in baseline autophagy levels relied predominantly on canonical nutrient-sensing pathways in murine but not human PDAC cells. Additionally, we found that autophagy flux was regulated independently of the cell cycle or the genetic status of p53 (i.e., allelic deletion, point mutation). Collectively, our results reveal conserved phenotypic outcomes but divergent mechanisms, underscoring the need for parallel comparative approaches before extrapolating findings from mouse PDAC models to human disease.