Abstract 1490: Elucidating the effect of glutamine metabolism in breast to bone metastasis

Abstract Bone-metastatic lesions will develop in approximately 65-75% of patients with metastatic breast cancer and are associated with high morbidity and mortality. Despite our limited understanding of how breast-to-bone metastases form, the recent emergence of metabolic adaptation as a critical factor in metastasis is a promising development. Breast cancer cells are particularly reliant on glutamine, a key amino acid that is metabolized by the enzyme glutaminase (GLS) to facilitate many downstream metabolic processes. Bone-tropic breast cancer cell lines significantly enhance their glutamine uptake, suggesting that glutamine metabolism may be a significant factor in bone metastasis. In addition to tumor cells, glutamine metabolism is critical for osteoblasts, important bone-resident cells that contribute to the “vicious cycle” of bone destruction during metastatic outgrowth in the bone niche. In this study, we sought to evaluate the role of glutamine metabolism in breast cancer bone metastasis by examining the effect of GLS function in metastasizing tumor cells and bone-native osteoblasts. Using an intracardiac inoculation model of bone metastasis, we found that breast cancer cells lacking GLS (GLS KO) failed to effectively form bone metastatic tumors. We also observed that GLS KO bone tumors show a reduction in osteolysis using a direct intratibial injection model. Mechanistically, we have found that GLS KO breast cancer cells develop a “senescence-like” phenotype that may limit metastatic outgrowth within the bone. To investigate the importance of glutamine metabolism in the bone niche, we developed a conditional genetic mouse model to delete GLS in osterix-expressing in osteoblast progenitors and mature osteoblasts (GLSOBKO). Remarkably, we observed reduced bone destruction in GLSOBKO mice after intratibial injection of syngeneic breast cancer cells. We also report a reduction in the number of osteoclasts at the bone/tumor interface in these mice, suggesting that loss of osteoblast GLS could temporarily halt the “vicious cycle” of bone metastasis. Together, this work suggests that glutamine metabolism may promote breast-to-bone metastasis via both intrinsic and extrinsic mechanisms. These findings raise the possibility of using pre-existing cancer therapies targeting glutamine metabolism to ameliorate bone metastatic burden in breast cancer. Citation Format: Breelyn A. Karno, Yoonha Hwang, Rachelle Johnson, Jin Chen, Deanna Edwards. Elucidating the effect of glutamine metabolism in breast to bone metastasis [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 1490.