A conserved epithelial wound-like transcriptional program driven by FOSL1 underlies malignant progression of pancreatic ductal adenocarcinoma (ATAC-Seq)

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest common malignancy. Benign lesions named pancreatic intraepithelial neoplasia (PanIN) are important precursors to PDAC, but these are extremely common in the general population. The mechanisms underlying the lethal conversion of benign PanINs to invasive PDAC is poorly understood. Here we harness Stereo-seq, a high resolution spatial transcriptomic profiling platform, to identify a core transcriptional program associated with invasive growth in human PDAC. This program, highly conserved in mice, is primarily comprised of genes activated to drive the migration of keratinocytes during wound healing in the skin. Genes of this wound-like program are required for conversion of PanINs into invasive PDAC in mice. Benign PanINs continually produce a small reservoir of wound-like cells that activate key tumor suppressor genes (TSGs), keeping the incipient malignant cells in check. TSG KO in PanIN leads to rapid outgrowth of the wound-like population, unleashing invasive growth. Wound-induced AP-1 transcription factors (TFs) FOSL1 and JUNB are specifically activated in invasive PDAC cells and enforced expression of FOSL1 in PanIN drives wound-like gene expression and benign-to-malignant plasticity. Malignant PDAC cells are surrounded by a conserved population of CTHRC1-expressing cancer-associated fibroblasts (CAFs) that possess a transcriptional program strikingly similar to one activated in a population of wound-emergent fibroblasts in skin. Bidirectional interactions between malignant cancer cells and the wound-like CAFs result in a feedback loop that enforces the malignant state.