Osteosarcoma is the most common primary malignant bone tumor in childhood. Patients who present with metastatic disease at diagnosis or relapse have a very poor prognosis, and this has not changed over the past four decades. The Wnt signaling pathway plays a role in regulating osteogenesis and is implicated in osteosarcoma pathogenesis. DKK-1 inhibits the canonical Wnt signaling pathway, causing inhibition of osteoblast differentiation and disordered bone repair. Our lab previously demonstrated that an mAb against DKK-1 prevented metastatic disease in a mouse model. This study expands upon those findings by demonstrating similar results with a small-molecule inhibitor of DKK-1, WAY262611, both in vitro and in vivo. WAY262611 was evaluated in vitro on osteosarcoma cell lines, including proliferation, caspase activation, cell-cycle analysis, and signaling pathway activation. We utilized our orthotopic implantation/amputation model of osteosarcoma metastasis in vivo to determine the impact of WAY262611 on primary tumor progression and metastatic outgrowth of disseminated tumor cells. Differentiation status was determined using single-cell RNA sequencing. We show here that WAY262611 activates canonical Wnt signaling, enhances nuclear localization and transcriptional activity of β-catenin, and slows proliferation of osteosarcoma cell lines. We also show that WAY262611 induces osteoblastic differentiation of a patient-derived xenograft of osteosarcoma in vivo, as well as inhibiting metastasis. This work credentials DKK-1 as a therapeutic target in osteosarcoma, allowing for manipulation of the Wnt signaling pathway and providing preclinical justification for the development of new biologics for the prevention of osteosarcoma metastasis.

This content is only available via PDF.
You do not currently have access to this content.