Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression

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SUMMARYTumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment.Graphical AbstractHighlightsTAMs in PDAC are derived from both monocytes and embryonic macrophagesTissue-resident embryonic macrophages promote PDAC progressionEmbryonically derived tissue-resident TAMs expand in PDAC via in situ proliferationEmbryonically derived TAMs exhibit unique pro-fibrotic activitiesZhu et al. identify tissue-resident macrophages of embryonic origin as a source of tumor-associated macrophages in pancreatic ductal adenocarcinoma. These cells expand through in situ proliferation during tumor progression and demonstrate a unique pro-fibrotic transcriptional profile distinct from that of their monocyte-derived counterparts.

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