NELL-1 regulates the matrisome to alter osteosarcoma disease progression

Sarcomas produce 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 non-neoplastic osteoinductive effects, yet highly expressed in skeletal sarcomas. Here, NELL1 gene deletion markedly reduced invasive behavior across human osteosarcoma (OS) cell lines. This resulted in reduced OS disease progression, inhibited metastatic potential and improved survival in a xenograft model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb driven sarcomagenesis, including reduced tumor frequency, and extended tumor free survival. Transcriptomic and phospho-proteomic analysis demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culture on OS enriched matricellular proteins reversed phenotypic and signaling changes among NELL1 knockout sarcoma cells. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma matrix, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short circuit sarcoma disease progression.