Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma

Abstract Activation of cellular signaling pathways by crosstalk between tumor cells and their microenvironment is an essential mechanism supporting pancreatic carcinogenesis. 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. Systemic blockade of ADAM17 significantly reduced tumor burden and suppressed activation of EGFR and STAT3, which are associated with two pro-tumoral signaling pathways. In addition, we found an elevated level of CCL21 in the MEDI3622-treated tumors resulting in increased tumor infiltration by dendritic cells and cytotoxic T cells as well as low infiltration of G-MDSC (granulocytic myeloid-derived suppressor cells). These results demonstrate a pronounced anti-tumor effect by ADAM17 blockade and indicate ADAM17 as a therapeutic target of pancreatic cancer. Citation Format: Hui-Ju Wen, Jacee Moore, Erick Davis, Daniel Long, Justin Lee, Brian Devorkin, Howard Crawford. Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B080.