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

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.