RYK promotes the stemness of glioblastoma cells via the WNT/ β-catenin pathway

// Assunta Adamo 1 , Danilo Fiore 1 , Fabio De Martino 1 , Giuseppina Roscigno 1, 2 , Alessandra Affinito 1 , Elvira Donnarumma 3 , Ilaria Puoti 1 , Lucia Ricci Vitiani 4 , Roberto Pallini 5 , Cristina Quintavalle 1 , Gerolama Condorelli 1, 2 1 Department of Molecular Medicine and Medical Biotechnology, “Federico II” University of Naples, Naples, Italy 2 IEOS, CNR, Naples, Italy 3 IRCCS-SDN, Naples, Italy 4 Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy 5 Institute of Neurosurgery, Universita Cattolica del Sacro Cuore, Rome, Italy Correspondence to: Gerolama Condorelli, email: gecondor@unina.it Keywords: glioblastoma, stem cells, ryk, β-catenin Received: September 06, 2016      Accepted: December 27, 2016      Published: January 09, 2017 ABSTRACT Glioblastoma multiforme (GBM) is characterized by a strong self-renewal potential and a poor differentiation state. Since receptor-like tyrosine kinase (RYK) activates the WNT/β-catenin pathway essential for cancer stem cell maintenance, we evaluated its contribution in conferring stemness to GBM cells. Here, we report that Ryk (related-to-receptor tyrosine kinase), an atypical tyrosine kinase receptor, is upregulated in samples from GBM patients as well as in GSCs. Ryk overexpression confers stemness properties to GBM cells through the modulation of the canonical Wnt signaling and by promoting the activation of pluripotency-related transcription factor circuitry and neurosphere formation ability. In contrast, siRNA-mediated knockdown of Ryk expression suppresses this stem-like phenotype. Rescue experiments reveal that stemness-promoting activity of Ryk is attributable, at least in part, to β-catenin stabilization. Furthermore, Ryk overexpression improves cell motility and anchorage independent cell growth. Taken together, our findings demonstrate that Ryk promotes stem cell-like and tumorigenic features to glioma cells its essential for the maintenance of GSCs and could be a target of novel therapies.