NELL1 Regulates the Matrisome to Promote Osteosarcoma Progression

Sarcomas produce an abnormal extracellular matrix (ECM), which in turn provides instructive cues for cell growth and invasion. Neural EGF like-like molecule 1 (NELL1) is a secreted glycoprotein characterized by its nonneoplastic osteoinductive effects, yet it is highly expressed in skeletal sarcomas. Here, we show that genetic deletion of NELL1 markedly reduces invasive behavior across human osteosarcoma (OS) cell lines. NELL1 deletion resulted in reduced OS disease progression, inhibiting metastasis and improv-ing survival in a xenograft mouse model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb-driven sarcomagenesis, which reduced tumor frequency and extended tumor-free survival. Transcriptomic and phospho-proteomic analyses demonstrated that NELL1 loss skews the expres-sion of matricellular proteins associated with reduced FAK signal-ing. Culturing NELL1 knockout sarcoma cells on wild-type OS-enriched matricellular proteins reversed the phenotypic and sig-naling changes induced by NELL1 deficiency. In sarcoma patients, high expression of NELL1 correlated with decreased overall sur-vival. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma ECM, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short-circuit sarcoma disease progression. Significance: NELL1 modulates the sarcoma matrisome to pro-mote tumor growth, invasion, and metastasis, identifying the matrix-associated protein as an orchestrator of cell-ECM interac-tions in sarcomagenesis and disease progression.