| HRA004376
(Open Access)
|
We adopted multi-omics strategies, such as single-cell RNA sequencing (scRNA-seq), transcriptomics, multi-immunohistochemistry (mIHC), flow cytometry, and metabolomics to analyze chemo-treated samples from humans and mice to identify the critical macrophage subset for PDAC chemo-resistance. Furthermore, we utilized clinical samples, an orthotopic mouse model, and a transgenic mice model targeting proliferating resident macrophages to verify our findings. We found four major TAM subsets within PDAC, of which proliferating resident macrophage was strongly associated with poor clinical outcomes, and they were able to survive chemotherapy by producing more deoxycytidine (dC) and less deoxycytidine kinase (dCK) to reduce the absorption of gemcitabine. In addition, proliferating rMacrophage could promote fibrosis and immunosuppression in PDAC. Eliminating proliferating rMacrophage in the transgenic mouse model could alleviate the fibrosis and immunosuppression, thus re-sensitizing PDAC to chemotherapy. |
