Expression data from patient-derived pancreatic cancer organoids with gene engineering

Lineage plasticity often emerges in human cancer along with clinical progression and exposure to chemotherapy. Although lineage transition is evident in an aggressive subtype of human pancreatic cancer characterized by the loss of the ductal identity and manifestation of squamous cell-like features, the drivers of these processes have remained elusive. We here harmonized organoid technology, molecular profiling and gene engineering and found that the H3K27me3-mediated erasure of the ductal identity and lineage specifiers, and hijacking of the TP63-driven squamous-cell program provide environmental fitness. Induction and fixation of the squamous-cell identity was dependent on Wnt-deficient environment, whereas KDM6A loss or a hypoxic niche licensed tumor cells for squamous reprogramming. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of pancreatic cancer organoids with squamous features. Our results demonstrate how adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer, and provide insights into the principles and significance of lineage conversion in human cancer. We used microarray gene expression analysis to study the effect of delta-Np63 overexpression and TP63 knockout in patient-derived pancreatic cancer organoids or genetically engineered organoids.