TRPM7 maintains progenitor-like features of neuroblastoma cells: implications for metastasis formation
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Jeroen Middelbeek1, Daan Visser2,*, Linda Henneman2,*, Alwin Kamermans1, Arthur J. Kuipers1, Peter M. Hoogerbrugge1,3, Kees Jalink2, Frank N. van Leeuwen1
1Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
2Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
3Princes Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
*These authors have contributed equally to this work
Frank N. van Leeuwen, e-mail: [email protected]
Keywords: neuroblastoma, trpm7, metastasis, differentiation, snai2
Received: December 17, 2014 Accepted: February 08, 2015 Published: March 05, 2015
Neuroblastoma is an embryonal tumor derived from poorly differentiated neural crest cells. Current research is aimed at identifying the molecular mechanisms that maintain the progenitor state of neuroblastoma cells and to develop novel therapeutic strategies that induce neuroblastoma cell differentiation. Mechanisms controlling neural crest development are typically dysregulated during neuroblastoma progression, and provide an appealing starting point for drug target discovery.
Transcriptional programs involved in neural crest development act as a context dependent gene regulatory network. In addition to BMP, Wnt and Notch signaling, activation of developmental gene expression programs depends on the physical characteristics of the tissue microenvironment. TRPM7, a mechanically regulated TRP channel with kinase activity, was previously found essential for embryogenesis and the maintenance of undifferentiated neural crest progenitors. Hence, we hypothesized that TRPM7 may preserve progenitor-like, metastatic features of neuroblastoma cells.
Using multiple neuroblastoma cell models, we demonstrate that TRPM7 expression closely associates with the migratory and metastatic properties of neuroblastoma cells in vitro and in vivo. Moreover, microarray-based expression profiling on control and TRPM7 shRNA transduced neuroblastoma cells indicates that TRPM7 controls a developmental transcriptional program involving the transcription factor SNAI2. Overall, our data indicate that TRPM7 contributes to neuroblastoma progression by maintaining progenitor-like features.
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