Tumor-associated osteoclasts converge on a matrix-sulfation program across human bone tumors.

Introduction: Osteoclasts mediate the bone destruction that drives much of the morbidity of giant-cell tumor of bone, osteosarcoma, and skeletal metastasis, yet these large multinucleated cells are lost in droplet single-cell data and have never been defined as a disease cell state. Methods: We reanalyzed 378,936 cells from osteoclast-rich human bone tumors and reference datasets, using within-tumor comparisons and independent validation analyses to characterize shared osteoclast transcriptional programs across the three tumor classes. Results: Tumor osteoclasts from all three tumor classes converged on a shared 74-gene transcriptional program. The program showed high scores in osteoclasts and low scores in neighboring myeloid cells, reproduced across four cancers of origin and in an independent cohort of 38,361 osteoclasts, and centered on a glycosaminoglycan-sulfation and mineralization module comprising PAPSS2, UST, EXT1, and FAM20C. The enrichment held across donors, the program increased as human monocytes differentiated into osteoclasts, and it tracked mature-osteoclast abundance in an independent spatial cohort of human osteosarcoma. Osteoclasts expressing the program were associated with a collagen and CD44 signaling neighborhood, retained the canonical regulators PU.1, MITF, and NFATc1, and occupied the terminus of osteoclastogenesis. Discussion: Across biologically distinct bone cancers, tumor osteoclasts share a reproducible, maturation-associated state centered on matrix-sulfation biology.