Abstract C039: Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma

Abstract

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, inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. systemic inhibition of ADAM17 led to a reduction in tumor burden and a concomitant decrease in EGFR activation. These effects were observed exclusively in the immunocompetent animals, but not in the immunodeficient animals. It implicates that inhibition of tumor growth by MEDI3622 is highly dependent on the immune response. Furthermore, we found an elevated level of CCL21 in the MEDI3622-treated tumors resulting in increased tumor infiltration by dendritic cells and cytotoxic T cells for tumor killing. Altogether, ADAM17 blockade displays a pronounced anti-tumor effect, suggesting ADAM17 as a therapeutic target of pancreatic cancer. Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C039.