The functions of TAK1+CAF in pancreatic cancer microenvironment

[Background] Pancreatic ductal adenocarcinoma(PDAC) is one of the most highly malignant tumors which has complex microenvironment. Cancer-associated fibroblasts(CAF) interact directly and indirectly with various immune cells, stromal cells and cancer cells in the tumor microenvironment, which has heterogeneous populations such as myofibroblastic CAF(myCAF), and inflammatory CAF(iCAF). Transformed growth factor-beta 1 activated kinase-1(TAK1) constitutes the cellular hub for several cytokine-mediated signaling, which regulates inflammatory responses such as NF-κB. While, the role of TAK1 in CAFs is not clear. [Purpose]To explore TAK1 functions in CAFs in PDAC microenvironment.[Materials and Methods] CAFs were primary cultured from fresh resected pancreatic cancer specimens. Three-dimensional co-culture models of PDAC tumors and CAFs were made to explore whether iCAFs or myCAFs functions influenced by TAK1. Then we checked the functions of TAK1 positive CAFs using immunofluoresence assay, western blotting (WB) and so on. Next, C57BL/6 mice were subcutaneous injected with organoid mixed with CAFs from KPC mice. [Results]Interference with TAK1 in CAF inhibited tumor cell metastasis and induced myCAF markers increased but iCAF markers decreased, indicating TAK1 inhibitor transform partial iCAF to myCAF. Also TAK1 inhibitors decreased tumor growth and increased immune cell infiltration in the stroma in Vivo.[Conclusions]TAK1 has a possibility to be a therapeutic target focusing on the iCAF which is a conductor of immune system in PDAC.