Deciphering the regulatory role of ADAM8 in the PDAC tumor microenvironment

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options, driven in part by its immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) and neutrophils (TANs) contribute to tumor progression and immune evasion. A Disintegrin and Metalloproteinase 8 (ADAM8), a zinc-dependent protease, is strongly upregulated in PDAC and correlates with poor clinical outcomes, suggesting a regulatory role in tumor progression. METHODS: Wild-type (WT) and Adam8 knockout (A8KO) PDAC cell lines were generated using the CRISPR-Cas9 technique, and PDAC mouse models with or without Adam8 expression were established to investigate the role of ADAM8 in tumor and immune cells. In vitro assays, including Western blotting, qPCR, migration and invasion assays, proliferation assays, ELISA, cytokine and proteome analyses, as well as co-culture experiments with PDAC cells and either macrophages or neutrophils, were employed to assess the effects of ADAM8 on tumor-immune cell crosstalk. In parallel, in vivo WT and A8KO KPC models were generated, genotyped, and monitored to evaluate the impact of ADAM8 on survival, tumor growth, and immune cell recruitment within the PDAC TME. RESULTS: ADAM8 deletion reduced tumor cell proliferation and migration, associated with reduced activation of FAK/Src/STAT3 signaling and altered secretion of cytokines including GM-CSF, M-CSF, ICAM-1, and TNF-α. Co-culture assays demonstrated that ADAM8 enhanced reciprocal signaling between tumor cells and TAMs/TANs, promoting pro-oncogenic activation. Migration assays and in vivo analyses revealed that ADAM8 facilitated recruitment of macrophages and neutrophils in PDAC TME, while Adam8KO tumors exhibited reduced immune infiltration and altered macrophage polarization. CONCLUSION: Our findings demonstrate that ADAM8 promotes PDAC aggressiveness by enhancing tumor cell proliferation and migration, activating FAK/Src/STAT3 signaling, and driving macrophage and neutrophil recruitment through cytokine regulation. By orchestrating both tumor-intrinsic pathways and tumor-immune interactions, ADAM8 emerges as a key determinant of PDAC progression and a systemic target for therapeutic intervention.