GLIS3 marks a neural-like progenitor cell state that drives metastasis in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs and metastasizes despite intensive therapy. The neural-like progenitor (NRP) transcriptional program is enriched in residual disease after neoadjuvant chemotherapy and radiotherapy, but its basis has remained unclear. We hypothesized that NRP represents a regeneration program co-opted by tumors recovering from cytotoxic injury. NRP signatures were strongly enriched in normal pancreatic injury and regeneration, and NRP cancer cells co-expressed transcription factors involved in pancreatic development. Our data support cell-intrinsic contributions and implicate IL-1β-associated inflammatory signaling as a plausible microenvironmental driver of elevated NRP expression. To enable direct phenotypic comparison with other cancer cell states, we established isogenic mouse organoid overexpression models for transcription factors linked to NRP, classical, and basal-like states. Glis3 emerged as a key NRP-associated factor, promoting clonogenicity, tumor growth, and metastasis. These findings identify a clinically relevant developmental regeneration program that emerges in PDAC after treatment.