Abstract Osteosarcoma (OSA) is the most common primary bone cancer in children and adolescents, typically arising during rapid skeletal growth. A frequent feature of OSA is an osteoblastic phenotype with abnormal bone formation. Leucine-rich repeat containing 15 (LRRC15) is a cell-surface protein highly expressed in several solid tumors, particularly OSA. Our previous work identified LRRC15 as a key adhesion molecule regulating migration, invasion, and cell–extracellular matrix (ECM) interactions in OSA cells. Time-course single-cell transcriptomics of LRRC15 knockdown revealed dysregulation of several integrins. Integrins are αβ heterodimeric transmembrane receptors essential for cell–ECM adhesion and bidirectional signaling. The β1 subunit (ITGB1) is especially important in cancer, pairing with several α subunits to bind collagen, fibronectin, and laminin. LRRC15 depletion modestly reduced ITGB1 at both gene and protein levels. Collagen-binding integrins (ITGA1, ITGA10) and RGD-binding integrins (ITGAV, ITGB5) were similarly downregulated. Given the overlap between pathways affected by LRRC15 loss and integrin biology, we hypothesized that LRRC15 and ITGB1 may functionally interact to regulate OSA cell adhesion and migration. We generated CRISPR-Cas9 knockouts (KO) of LRRC15 and ITGB1 in OSA cell lines. Both LRRC15 and ITGB1 KO cells exhibited comparable defects in proliferation, migration, and spheroid invasion, suggesting a strong functional connection between these molecules. Quantitative mass spectrometry and western blots demonstrated decreased LRRC15 expression in ITGB1 KO cells, and reduced ITGB1 expression in LRRC15 KO cells. Notably, rescue of LRRC15 in KO cells resulted in elevated ITGB1 expression. Furthermore, to detect physical interaction, we performed immunoprecipitation with LRRC15 using extracts from parental and LRRC15 KO cells, followed by immunoblotting with an ITGB1 antibody. A significantly lower ITGB1 signal was detected in LRRC15 KO cells. Similarly, when immunoprecipitation was performed with an ITGB1 antibody and detected by immunoblotting with an LRRC15 antibody, we observed reduced LRRC15 expression in ITGB1 KO cells. These findings indicate that ITGB1 and LRRC15 may physically interact with each other. Taken together, our findings indicate that LRRC15 may modulate integrin-mediated adhesion and signaling in OSA. Specifically, the interaction between LRRC15 and integrin β1 appears critical for maintaining integrin-dependent pathways that drive cell proliferation, migration, and invasion. Further mechanistic studies will be required to delineate the molecular basis of this interaction and its contribution to tumor progression and metastasis Citation Format: Sanjit Mukherjee, Wei-Dong Chen, Lisa M. Jenkins, Yuelin Zhu, Marbin Pineda, Robert Walker, Paul S. Meltzer. LRRC15-Integrin β1 connection in osteosarcoma cells: Linking adhesion to invasion 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 3483.
Mukherjee et al. (Fri,) studied this question.