Basal-to-classical phenotypic switch of pancreatic cancer cells upon integration into the duodenal epithelium

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors. Based on transcriptomic classifiers, basal-like and classical PDAC subtypes can be defined that differ in prognosis. Single-cell sequencing has recently revealed that these subtypes coexist in individual tumors. However, the contribution of either clonal heterogeneity or microenvironmental cues to subtype heterogeneity is unclear. Here, we report the tumor phenotype dynamics in a cohort of patients in whom PDAC infiltrated the duodenal wall. Using multiplex immunohistochemistry, we show that PDAC cells revert to non-destructive growth and undergo differentiation towards the classical subtype upon integration into the duodenal epithelium. Our results tightly link microenvironmental cues to the PDAC molecular subtype and open the door to a systematic investigation of microenvironmental control in human pancreatic cancer.