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.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor and one of the most devastating human malignancies
These findings indicate that receptor-like tyrosine kinase (RYK) is strongly upregulated in GBM stem cells and are suggestive of a possible role of this receptor in the promotion of stemness
RYK is an atypical member of the receptor tyrosine kinase (RTK) family able to function as a WNT co-receptor and activate the canonical β-catenin-dependent pathway
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor and one of the most devastating human malignancies. Recent studies have suggested that this tumor arises from a small population of cancer stem cells (CSCs, or tumor-initiating cells). CSCs retain many properties of normal neural stem cells (NSCs), such as self-renewal and multipotency [1, 2]. They are believed to constitute the tumor’s driving force and to be responsible for tumor recurrence and radio- and chemo-resistance [3,4,5,6]. Blocking self-renewal signaling by targeting surface markers or forcing differentiation of GBM CSCs (GSCs) may represent potential effective therapeutic strategies for GBM. Poor understanding of the molecular pathways involved in CSCs expansion and maintenance has hindered the development of such approaches
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