Abstract C069: A conserved reepithelialization program driven by FOSL1 underlies malignancy in pancreatic ductal adenocarcinoma

Abstract Benign lesions named pancreatic intraepithelial neoplasia (PanIN) are frequent in the healthy population but are precursors to deadly pancreatic ductal adenocarcinoma (PDAC). Conversion of PanINs to PDAC is poorly understood. Here we harness high resolution spatial transcriptomics to identify a core transcriptional program associated with invasive growth across human PDAC and required for PanIN-to-PDAC progression in mice. The malignancy program is lineage restricted, and predominantly comprised of transcripts activated to drive reepithelialization during skin wound healing. This wound-like program appears in rare PanIN cells that also activate tumor suppressor genes (TSGs), which keep the incipient malignant cells in check. TSG KO in PanINs leads to rapid outgrowth of the wound-like population, unleashing invasive growth, driven by the wound-induced TF FOSL1. Bidirectional interactions between malignant epithelial cells and wound-like CTHRC1-expressing CAFs enforce the malignant state. Our results suggest that wound recapitulation drives the highly invasive properties of PDAC. Citation Format: Charles David, Melian Zhuo, Yong Li, Yifeng Zhang, Chenlu Yang, Ziqing Deng, Yupei Zhao, Wennming Wu, Junya Peng, Mo Chen. A conserved reepithelialization program driven by FOSL1 underlies malignancy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C069.