Abstract P6-12-05: The role of endothelial-specific AXL and its associated signaling pathways in the tumor microenvironment

Abstract

Abstract Most breast cancer deaths result from the development of metastases. The complex tumor microenvironment provides signals that can instruct both breast cancer cells to invade and tumor blood vessels to be leaky, hence supporting metastasis. We identified the receptor tyrosine kinase (RTK) AXL to be essential for metastasis. Genetic ablation of Axl in mouse models of HER2+ breast cancer, either globally or specifically in mammary epithelial cells, blunts metastasis but not primary tumor growth. We found that Axl expressed in tumor cells contributes to the remodeling of the tumor microenvironment, including immune cell recruitment and abnormal blood vessels. Hence, AXL in epithelial cells promotes cell invasion and shapes a pro-metastatic microenvironment that would be poorly responding to treatments such as immunotherapy. While AXL is known to be expressed on endothelial cells, its endothelial function has yet to be clearly defined. This project aims to address the hypothesis that AXL expressed on endothelial cells promotes processes that lead to abnormal blood vessel formation to promote metastasis. To address this hypothesis, we first studied the specific intracellular interactions between two RTKs, AXL and the known pro-angiogenic receptor VEGFR. Our preliminary analyses indicates that GAS6 can not only induce the phosphorylation of the permeability marker eNOS on its own but can also potentiate the VEGF’s response. The index of linearity of the endothelial tight junctions upon GAS6 stimulation show increased permeability of the endothelial cells. To further characterize the signaling pathways controlled by these receptors, we plan to perform a phosphoproteomics screen. We will focus on studying the AXL+VEGFR phosphoproteome and define the signaling pathways that impact vascular permeability. The most interesting candidate(s) will be studied in the context of mouse tumor models. In parallel, we are generating a conditional deletion of Axl in endothelial cells by crossing Axlfx/fx mice with Pdgfb:iCreER animals. With this, we will study the specific endothelial effects of Axl in vivo, specifically with vessel permeability and retinal angiogenesis assays. Multiple anti-angiogenic therapies for cancer failed in the clinic highlighting the need for new strategies to target endothelial cells in cancer. This project will provide essential information on the role of endothelial specific AXL, in the context of the HER2 breast cancer, and of its downstream effectors. With more specific targets, anti-angiogenic therapies could decrease their off-target effects and increase their efficacy in the clinic. This project has the potential to uncover therapeutic targets that could reduce the metastatic burden in breast cancer patients, and therefore better the prognostic for the HER2 cancer subtype. Citation Format: Andréane Lalonde, Jean-François Côté. The role of endothelial-specific AXL and its associated signaling pathways in the tumor microenvironment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-12-05.