This sentence defines the central question of the study. Although pancreatic ductal adenocarcinoma has ductal morphology, it remains unclear whether precursor lesions arise from true ductal cells or from acinar cells that undergo reprogramming. The authors test whether oncogenic KRAS expands existing ductal cells or instead drives acinar cells to adopt a duct-like state through factors such as Sox9. Defining this distinction is essential for identifying the true cell of origin in PDA.

This sentence highlights the main scientific problem the study is addressing. Just because mutations like KRAS and TP53 are commonly found in pancreatic cancer does not prove they are sufficient or that they must occur together to cause disease. Observing mutations in patient samples cannot determine causation. Therefore, the authors use a genetically engineered mouse model to systematically test whether combining KrasG12D and Trp53R172H is enough to drive invasive and metastatic PDA.