Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions

The adult healthy human pancreas has been poorly studied given the lack of indica-tion to obtain tissue from the pancreas in the absence of disease and rapid post-mortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individu-als irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fi broblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. SIGNIFICANCE: Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell -intrin-sic factors that restrain or, conversely, promote malignant progression.

Automated summary

We characterized the unique microenvironment of the adult human pancreas and discovered the high prevalence of PanIN lesions compared to pancreatic cancer. Fibroblasts and macrophages in pancreatic cancer and peritumoral tissue showed distinct transcriptomic signatures. PanIN epithelial cells in healthy pancreas exhibited remarkable similarity to cancer cells transcriptionally, suggesting early initiation of neoplastic pathways in tumorigenesis.