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…
Pancreatic cancer's progression from early pancreatic intraepithelial neoplasia (PanINs) remains unclear. A mouse model study reveals Early Progression Cells (EPCs) as a new entity, a stem-like population of cancer stem-like cells, arising from rare KrasG12D cells. EPCs are stress-adapted, inflammation responsive stem cells, upregulating gene programmes associated with microenvironment remodelling.
These cells are prevalent in early metaplastic stages and PanIN progression from low to high grade, but less frequent in tumours. EPCs exhibit stem cell characteristics in vitro and rely on Nupr1 stress response pathways for survival. A novel cell-cell interaction, APP-CD74, links EPCs with neighbouring epithelial cells in PanINs and tumours.
Inhibiting CD74 activity causes high-grade PanIN organoid death, indicating EPCs' critical role in high-grade PanINs. Spatial transcriptomics in human samples detects EPC gene signatures in human PanIN and pancreatic ductal adenocarcinoma (PDAC) tissues, including APP-CD74 interactions, suggesting EPCs' relevance to human disease.
Further understanding of EPC biology could uncover new insights into why rare PanINs progress toward tumours.
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