Abstract 7225: The secreted cytokine Chitinase 3-like-1 promotes breast cancer metastasis

Abstract Breast cancer is the second most common cancer and a major cause of mortality affecting women worldwide. Immunosuppression is a key hallmark of cancer progression, whereby cancer cells suppress the immune system that is programmed to fight the disease. This suppressed tumor immune microenvironment (TIME) facilitates cancer metastatic spread to distant organs, which is associated with treatment resistance, recurrence, and poor prognosis. The Signal transducer and activator of transcription 3 (Stat3) suppresses the immune system, drives cancer progression and metastasis. Genetic ablation of Stat3 in the murine inducible breast tumor model expressing polyoma virus middle T (PyMT), results in delayed tumor onset and reduced tumor growth and metastasis. We have also previously demonstrated that the secreted protein Chitinase 3-like-1 (Chi3l1) is a direct target of Stat3 which promotes immunosuppression through its actions on neutrophils. Chi3l1 recruits neutrophils and induces the formation of Neutrophil Extracellular Traps (NETs) that block T cells from infiltrating the tumor. Targeting both Chi3l1 or neutrophils resulted in increased T cell infiltration and delayed tumor onset. However, the roles of Chi3l1 during the metastatic cascade remained unclear. To further investigate the role of Chi3l1 in metastasis, we generated a novel inducible mouse model that overexpresses Chi3l1 specifically in the mammary epithelial cells. Overexpression of the Chi3l1 protein in the Stat3 knockout PyMT model showed a rescue of the delay in tumor onset. Consistent with our previous studies, Chi3l1 overexpression caused a dramatic influx of neutrophils and the generation of an immune suppressed TIME. In addition, we observe an increase in circulating tumor cells which correlated with a quicker onset and increased incidence of pulmonary metastasis. These results hint that in breast cancer, Chi3l1 overexpression creates a pro-tumorigenic TIME which favorizes tumor initiation and progression as well as induces intravasation of tumor cells into the blood stream, which leads to metastasis to distant sites. Our future studies will investigate whether this phenotype is driven through neutrophils and whether targeting neutrophils would inhibit Chi3l1-mediated metastasis. Citation Format: Adeline Masse, Tarek Taifour, Yu Gu, Virginie Sanguin-Gendreau, Dongmei Zuo, Bin Xiao, Hailey Proud, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Rinath Jeselsohn, William J. Muller. The secreted cytokine Chitinase 3-like-1 promotes breast cancer metastasis [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 7225.