Early Progression Cells mark a stem-like state associated with pancreatic cancer initiation and progression

Pancreatic cancer is deemed to progress from microscopic pancreatic intraepithelial neoplasia (PanINs). However, low grade PanINs are frequently detected in the general population without presentation or increased risk of developing cancer, suggesting that many PanINs never progress to tumours. What precisely characterises PanINs that develop into tumours is insufficiently understood. Using a mouse model where pancreatitis-induced tissue injury promotes pancreatic cancer from rare KrasG12D cells, we identify Early Progression Cells (EPCs) as a new entity, a novel population of cancer stem-like cells. Transcriptomic analyses illustrate EPCs as stress-adapted, inflammation responsive stem cells that also upregulate gene programmes indicative of microenvironment remodelling. Using identified EPC protein markers, we show that EPCs are prevalent in early metaplastic stages and in PanIN progression from low grade to high grade but are rarer in tumours. PanIN- and tumour-derived sphere and organoid assays demonstrate that EPCs possess all characteristics of stem cells in vitro and are dependent on Nupr1 stress response pathways for survival and growth. We identify APP-CD74 as a novel cell-cell interaction pathway between EPCs and neighbouring epithelial cells in PanINs and tumours. Inhibition of CD74 activity in vitro induces high-grade PanIN organoid death, suggesting EPCs are critical for high-grade PanINs. Using spatial transcriptomics of human samples, we detect gene signatures of EPCs in distinct regions of human PanIN and PDAC tissues, including APP-CD74 interactions, providing compelling evidence that EPCs are relevant to human disease. Further understanding of EPC biology will likely uncover new knowledge on why rare PanINs progress towards tumours.