A conserved re-epithelialization program underlies malignancy in pancreatic ductal adenocarcinoma

Pancreatic intraepithelial neoplasia (PanIN) is common in healthy individuals, but can progress to invasive pancreatic ductal adenocarcinoma (PDAC). PanIN cells spread non-invasively throughout pancreatic ducts, while PDAC is defined by the ability to exit ducts and invade the parenchyma. Using high-resolution spatial transcriptomics, we identify a conserved epithelial program, MP10 that marks invasive cancer cells across human PDAC and is activated during PanIN-to-PDAC progression in mice. MP10 resembles the re-epithelialization program of wound-edge keratinocytes, including hemidesmosome components, integrins, and metabolic genes required for keratinocyte migration. Rare PanIN cells spontaneously activate MP10 while also triggering tumor suppressor genes (TSGs), which keep the incipient malignant cells in check. TSG loss unleashes these cells to invade the parenchyma, driven by the wound-induced transcription factor FOSL1. MP10-expressing cancer cells induce nearby CAFs into a wound-like CTHRC1^high state, which in turn promote neoplastic MP10 through EGFR activation, forming a wound-like loop that underlies invasive PDAC.