Abstract 6866: Investigating the role of Epha2 in breast cancer-mediated myeloid cell expansion and function
Authors: Parker Dominique , Ngwa Verra , Chen Jin , Rhoades Julie 
Published: March 2024

Abstract
Bone metastases are present in over 70% of metastatic breast cancer patients, and current therapy reduces osteolysis in tumor-induced bone disease (TIBD) but does not improve overall survival. Frequently, TIBD is characterized by an increase in osteoclast proliferation and bone-resorbing activity, and patients often experience pain and pathologic fractures. Increased bone resorption releases growth factors that aid in the progression of tumor growth causing the ‘vicious cycle’. Additionally, bone metastatic patients are often resistant to first- and second-line therapies highlighting an importance for research in this area. The receptor tyrosine kinase, Ephrin-type-A 2 receptor (EphA2), participates in both forward and reverse signaling during receptor/ligand engagement and participates in many physiological and pathological processes, including bone homeostasis, immunity, and cancer. Interestingly, EphA2 is highly expressed in bone metastases, and previous evidence suggests that EphA2 can promote TIBD and reduce anti-tumor immunity. We therefore hypothesize that increased expression of EphA2 in breast cancer cells at the site of bone metastasis promotes expansion of myeloid cells, leading to TIBD. Previous data shows a reduction in osteoclast number and bone lesions following EphA2 knockout. However, the mechanism by which EphA2 mediates the expansion of osteoclasts is not well understood. In agreement with previous work, our data shows that EphA2 deletion in murine breast cancer (BC) cell line, 4T1, reduces bone lesion area and number and the presence of bone metastasis-associated macrophages. Additionally, we observed a significant reduction in Ly6Chi cells. To assess the effects of EphA2 deletion on the behavior of 4T1 cells, we conducted a wound healing assay and observed a decrease in wound healing capacity in 4T1 cells following EphA2 deletion. This suggests that EphA2 expression in 4T1 cells may increase their metastatic potential. We will repeat these studies and incorporate factors from the bone marrow. Our future studies will investigate the role of EphA2 signaling and reverse signaling in BC cell lines, myeloid progenitor cells, osteoclasts, and bone metastasis-associated macrophages. We will utilize murine and human BC cell lines to elucidate the effects of EphA2 deletion in BC on immune cell populations, bone metastasis, and tumor progression. Additionally, we will investigate how EphA2 reverse signaling impacts osteoclasts’ ability to modulate immune cells. We aim to reduce TIBD and tumor burden by reducing the expansion of osteoclasts and shifting the immune cells to an anti-tumorigenic phenotype. Our studies will provide additional insight into the underlying mechanisms of the vicious cycle which will offer new treatment strategies for patients with osteolytic breast cancer.
Citation Format: Dominique Parker, Verra Ngwa, Jin Chen, Julie Rhoades. Investigating the role of Epha2 in breast cancer-mediated myeloid cell expansion and function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6866.