GLIS3 Marks a Neural-like Progenitor Cell State that Drives Metastasis in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has a high rate of recurrence and metastasis despite intensive therapy. The neural-like progenitor (NRP) transcriptional program is enriched in residual disease after neoadjuvant chemotherapy and radiotherapy; however, the mechanisms for increased NRP expression in the post-treatment setting remain unclear. Here, we find that NRP signatures are strongly enriched in tissue injury and regeneration, and NRP cancer cells co-express transcription factors involved in pancreatic development. We identify both cell autonomous and ligand mediated mechanisms for inducing NRP expression in vitro. We establish and characterize isogenic mouse organoid overexpression models for transcription factors associated with the NRP, classical, and basal-like states. We discovered that Glis3 is a key NRP-associated transcription factor that drives malignant properties including greater clonogenicity, tumor growth, and metastasis compared to isogenic models for the classical and basal-like states. Our work highlights the emergence of clinically relevant developmental regeneration programs in the post-treatment context.