Abstract 341: Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and will become the 2nd leading cause of cancer related death in the United States within the next 10 years. Lack of early symptoms and a poor response to current therapies make PDAC the deadliest of all major cancers. PDAC is characterized by a dense fibroinflammatory stroma which is composed of fibroblasts and immune cells and has been implicated to influence tumor progression and therapeutic outcome. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, systemic inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. Tumor regression was observed in the mice treated with MEDI3622 and was accompanied by high infiltration of cytotoxic T cells and low infiltration of G-MDSC (granulocytic myeloid-derived suppressor cells). In addition, activation of EGFR and STAT3, which are associated with two pro-tumoral signaling pathways, were reduced by MEDI3622. These results demonstrate a pronounced anti-tumor effect by ADAM17 blockage and indicate ADAM17 as a therapeutic target of pancreatic cancer. Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 341.