A pancreatic cancer organoid incorporating macrophages reveals the correlation between the diversity of tumor-associated macrophages and cancer cell survival

Pancreatic ductal adenocarcinoma (PDAC) is a progressive cancer with a poor prognosis. It contains a complex tumor microenvironment (TME) that includes various stromal cell types. Comprehending cellular communications within the TME is difficult due to a lack of research models that can recapitulate human PDAC-TME. Previously, we recapitulated, in part, the PDAC-TME containing a diversity of cancer-associated fibroblasts (CAFs) in vitro. This was done by establishing a PDAC organoid by co-culturing patient-derived cancer cells with human induced pluripotent stem cell (hiPSC)-derived mesenchymal and endothelial cells, which was designated the fused pancreatic cancer organoid (FPCO). We further incorporated macrophages derived from the THP-1 cell line, which are the source of tumor-associated macrophages (TAMs), a major TME component, into FPCO, which was designated M0-FPCO. Bulk RNA sequencing (RNAseq) analysis revealed that macrophages in M0-FPCO (FPCO-Mac) lost their pro-inflammatory features but acquired pro-angiogenic features. Consistently, the formation of an endothelial cell network was enhanced in M0-FPCO. Single-cell RNA-seq (scRNA-seq) analysis revealed that M0-FPCO contained five TAM subpopulations similar to the corresponding TAM in human PDAC tissue in the integrated analysis, including SPP1