Abstract Osteosarcoma (OS) is an aggressive bone cancer primarily found in children and young adults with a five-year survival rate that drops significantly in patients with metastatic disease. At diagnosis, around 20% of patients have lung metastases, reducing survival from 70% to 30%. We believe that an indicator of metastatic potential is the aberrant expression of Vascular Cell Adhesion Molecule 1 (VCAM-1) on the tumor surface as human OS tissues have been shown to overexpress this molecule; however, its precise role remains unclear. We hypothesize that the interaction between VCAM-1 on OS cells and its receptor, the α4β1 integrin (VLA-4) on macrophages, contributes to the ability of OS to metastasize. Our preliminary evidence suggests that tumorigenic effects of VCAM-1 are isoform dependent, and truncated VCAM-1 is critically important to metastasis. Our research model uses bone marrow-derived macrophages exposed to murine OS cell lines K7 and K7M2, the latter being highly metastatic. Early data show that VCAM-1-VLA-4 binding induces a pro-tumoral macrophage phenotype, upregulating Arginase 1, an M2 macrophage marker. Currently, we are investigating whether this effect is specifically driven by the truncated isoform and exploring the role it plays in the PI3K-AKT signaling pathway. We plan to evaluate this hypothesis by looking at expression of the proteins in this signaling axis on bone marrow derived macrophages (BMDMs) that have been influenced by the aforementioned osteosarcoma cell lines. By elucidating how VCAM-1-VLA-4 interactions drive macrophage polarization, we aim to identify novel therapeutic targets that could shift macrophage behavior and improve treatment outcomes in OS. Citation Format: Daniel Kingsley, Sung Hee Choi, Jay Myers, Alex Y. Huang. Osteosarcoma exploits macrophage VCAM1-VLA4 signaling axis to facilitate pulmonary metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6125.
Kingsley et al. (Fri,) studied this question.