SPP1+ Venous Endothelial Cells and CRABP2+ Tumor Cells Contribute to Favorable Body and Tail Pancreatic Ductal Adenocarcinoma Tumor Microenvironment

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy; however, no validated treatments are currently available. Clinically, the tumor position, head and uncinate process (HU), or body and tail (BT) of the pancreas are vital for surgical strategies; however, fundamental research has seldom revealed the heterogeneous tumor microenvironment (TME) among different types of PDAC. Here, we applied multicohort single‐cell and spatial RNA‐seq methods together with patient‐derived organoid models to reveal the TME heterogeneity between HU and BT PDAC. Osteopontin, encoded by SPP1 , is secreted by vessel endothelial cells in BT PDAC and is associated with increased tumor burden. The number of tumor cells marked by CRABP2 was lower in BT PDAC and was identified as a prognostic marker of overall survival, as well as CD8 + T‐cell infiltration. The expression of CRABP2 was also validated to be downregulated in BT PDAC in patient‐derived organoid models. Overall, we profiled the heterogeneous PDAC TME between HU and BT PDAC, which could provide novel insight into the relationships between clinical characteristics and TME molecular research.