Pancreatic cancer: from the first Kras mutant cell to tumours
Beatriz Salvador Barbero
Queen Mary University of London, John Vane Science Centre
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with a very poor survival rate. Understanding why some pancreatic premalignant lesions progress to cancer while others remain indolent is critical for developing strategies for early intervention.
Pancreatic cancer initiation is driven by oncogenic KRAS, which can induce acinar-to-ductal metaplasia (ADM) and the formation of pancreatic intraepithelial neoplasias (PanINs). We hypothesised that a distinct subset of KRAS-mutant cells, termed Early Progression Cells (EPCs), acquires stem-like properties that promote PanIN progression.
Using a genetically engineered mouse model of pancreatic cancer initiation, combined with single-nucleus RNA sequencing, spatial transcriptomics and functional assays, we identified a distinct epithelial population with enhanced stem-like, KRAS/MAPK and stress-resistance programs. EPCs were enriched in a subset of low- and high-grade PanINs, suggesting that their presence may identify lesions with increased progression potential. Trajectory analyses positioned EPCs as a central progenitor-like population, while functional assays demonstrated enhanced self-renewal capacity.
We further identified an APP–CD74 interaction between EPCs and neighbouring epithelial cells. Spatial and protein-level analyses confirmed this interaction, while CD74 inhibition impaired organoid growth, highlighting a potential vulnerability during early pancreatic cancer development. Importantly, these cellular and molecular features were also observed in human PanIN and PDAC samples.
Together, our findings identify PCDCs as a stem-like epithelial population associated with PanIN progression and reveal potential therapeutic vulnerabilities that could be exploited to intercept pancreatic cancer before invasive disease develops.