Abstract 2634: IL34-induced Arg1 positive macrophage cells at the edge of invasion in cerebellum metastasis model of HER2-positive breast cancer

Abstract Brain metastases occur in about 30% breast cancer patients. The cerebellum is a frequent location for metastases in HER2-positive breast cancer patients, but the mechanisms for this is unknown. We hypothesize that the cerebellar microenvironment plays a crucial role in promoting the growth of metastatic HER2+ breast cancer cells. To study the interaction between cerebellar cells and metastatic breast cancer, we developed a syngeneic, immunocompetent mouse model for breast cancer brain metastasis, by stereotactically injecting mouse breast cancer organoids with HER2V777L; PIK3CAH1047R activating mutations or HER2V777L; TP53fl/fl1 into the cerebellum. Growth of these cerebellar metastasis was monitored both by MRI and also with Herceptin imaging using a Near-Infrared fluorophore conjugated to Herceptin. We observed significant tumor growth in the cerebellum for up to 7 weeks post injection. We further investigated cellular interactions within the pro-tumorigenic microenvironment and HER2+ breast cancer cells using spatial transcriptomics. We identified inflammation-induced ARG1+ macrophage cells at the edge of the cerebellar metastasis. Further, the cytokine IL34 is upregulated in the brain metastasis. IL34, which is secreted by HER2+ breast cancer, induces Arg1 expression in both homeostatic microglial cells and bone marrow derived macrophages. These results suggest IL34 polarizes macrophages facilitating tumor invasion in the brain. These novel mouse models and findings elucidate the molecular mechanisms and the role of the tumor microenvironment that promotes cerebellar metastasis, and suggest a therapeutic approach to inhibit breast cancer invasion into the brain. Citation Format: Xiaoqing (Cathy) Cheng, Khooshbu Kantibhai Patel, Yiwei Fu, Ryan Cleary, Brandon Zhou, Maureen Highkin, Jacob Hsia, Xiaohua Jin, Julie L. Prior, Megan Michie, Rui Sun, Ian S. Hagemann, Tristan Li, Vaibhav Jain, Simon Gregory, Albert Kim, Ron Bose. IL34-induced Arg1 positive macrophage cells at the edge of invasion in cerebellum metastasis model of HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2634.