Abstract PR002: Longitudinal study of bone marrow adipocytes throughout tungsten-enhanced breast cancer metastasis

Abstract Tungsten is classified as an emerging environmental toxicant due to increased human exposure and lack of knowledge of the health risks. Epidemiological and in vivo studies demonstrate that exposure to tungsten contributes to the carcinogenic process, but the molecular mechanisms remain unclear. Due to a cohort of breast cancer patients accidentally exposed to tungsten during intraoperative radiotherapy, our lab is investigating the effects of tungsten exposure on breast cancer progression and metastasis. Tungsten is known to accumulate in the bone, creating a site for long-term exposure and toxicity. Breast cancer is also known to metastasize to the bone. Previous research in our lab has shown that in multiple triple-negative breast cancer orthotopic models, tungsten enhances breast cancer metastasis to the bone. These findings suggest that tungsten deposition in the bone creates a favorable microenvironment to promote metastasis. Bone marrow adipocytes (BMA) play an important role in breast cancer metastasis to the bone through the secretion of adipokines that drive tumor cells homing, colonization, and growth by changing the microenvironment. Research also suggests that breast cancer cells arrive in the bone in as little as 10 days in murine models, starting the colonization and remodeling process. We aim to understand the changes in BMA throughout the metastatic process to inform the effect tungsten plays in changing these BMA, to enhance breast cancer metastasis to the bone. 6-8 week old female BALB/c and C57BL/6 mice were exposed to 15ppm tungsten (W) in their drinking water or tap water (CTL) for 4 weeks. After 4 weeks of exposure, mice underwent orthotopic injections of 4T1 (BALB/c) or E0771-Luc (C57BL/6) cells into the 4th mammary fat pad. Longitudinal time points were conducted to track changes after 4 weeks of exposure to tungsten with no tumor cell injection, 2 weeks and 3 weeks post-tumor cell injection. At the end of each study, bones were collected for multiple parameters. Femurs were used for IHC staining of Perilipin-1+ (Plin1+) adipocytes within the bone marrow. Bone marrow from tibiae were cultured to select for mesenchymal stromal cells (MSCs), which were differentiated into BMA through media selection. Cell supernatant and RNA were collected from both MSCs and BMA to profile changes in adipokines and cytokines throughout the metastatic process. The BALB/c model had more changes in adipocyte secretion and numbers, which were not mirrored in the C57BL/6 model, suggesting differences in adipocyte function within each model. However, CXCL2 expression was increased with tungsten exposure in both models, perhaps a potential key player in enhanced metastasis to the bone. Understanding adipokine/cytokine expression and their influence on the bone microenvironment will help narrow down possible key players that tungsten influences. These insights could prove to be valuable in better elucidating how tungsten targets the bone niche to drive breast cancer metastasis. Citation Format: Charlotte M. McVeigh, Jennifer A. Tjung, Jorge L. Moreno, Sydnee J. Yazzie, Lauren K. Heine, Grace A. Picha, Serena C. Helewicz, Guy W. Herbert, Sebastian Medina, Alicia M. Bolt. Longitudinal study of bone marrow adipocytes throughout tungsten-enhanced breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr PR002.