Urokinase Receptor uPAR Downregulation in Neuroblastoma Leads to Dormancy, Chemoresistance and Metastasis

Simple Summary uPAR is a membrane receptor that contributes to extracellular matrix remodeling and controls cellular adhesion, proliferation, survival, and migration. We demonstrate that the initially high uPAR expression predicts poor survival in neuroblastoma. However, relapsed neuroblastomas have a significantly decreased uPAR expression. uPAR downregulation in neuroblastoma cells leads to dormancy and resistance to chemotherapeutic drugs. In mice, low uPAR-expressing neuroblastoma cells formed smaller primary tumors but more frequent metastasis. uPAR is a membrane receptor that binds extracellular protease urokinase, contributes to matrix remodeling and plays a crucial role in cellular adhesion, proliferation, survival, and migration. uPAR overexpression in tumor cells promotes mitogenesis, opening a prospective avenue for targeted therapy. However, uPAR targeting in cancer has potential risks. We have recently shown that uPAR downregulation in neuroblastoma promotes epithelial-mesenchymal transition (EMT), potentially associated with metastasis and chemoresistance. We used data mining to evaluate the role of uPAR expression in primary and relapsed human neuroblastomas. To model the decreased uPAR expression, we targeted uPAR using CRISPR/Cas9 and shRNA in neuroblastoma Neuro2a cells and evaluated their chemosensitivity in vitro as well as tumor growth and metastasis in vivo. We demonstrate that the initially high PLAUR expression predicts poor survival in human neuroblastoma. However, relapsed neuroblastomas have a significantly decreased PLAUR expression. uPAR targeting in neuroblastoma Neuro2a cells leads to p38 activation and an increased p21 expression (suggesting a dormant phenotype). The dormancy in neuroblastoma cells can be triggered by the disruption of uPAR-integrin interaction. uPAR-deficient cells are less sensitive to cisplatin and doxorubicin treatment and exhibit lower p53 activation. Finally, low uPAR-expressing Neuro2a cells formed smaller primary tumors, but more frequent metastasis in mice. To the best of our knowledge, this is the first study revealing the pathological role of dormant uPAR-deficient cancer cells having a chemoresistant and motile phenotype.

Automated summary

The expression of uPAR in neuroblastoma is associated with patient survival. High uPAR expression predicts poor survival, while relapsed neuroblastomas show significantly decreased uPAR expression. Downregulation of uPAR in neuroblastoma cells leads to dormancy and resistance to chemotherapy.