title: The TRPM7 interactome defines a cytoskeletal complex linked to neuroblastoma progression.
abstract: Neuroblastoma is the second-most common solid tumor in children and originates from poorly differentiated neural crest-derived progenitors. Although most advanced stage metastatic neuroblastoma patients initially respond to treatment, a therapy resistant pool of poorly differentiated cells frequently arises, leading to refractory disease. A lack of insight into the molecular mechanisms that underlie neuroblastoma progression hampers the development of effective new therapies for these patients. Normal neural crest development and maturation is guided by physical interactions between the cell and its surroundings, in addition to soluble factors such as growth factors. This mechanical crosstalk is mediated by actin-based adhesion structures and cell protrusions that probe the cellular environment to modulate migration, proliferation, survival and differentiation. Whereas such signals preserve cellular quiescence in non-malignant cells, perturbed adhesion signaling promotes de-differentiation, uncontrolled cell proliferation, tissue invasion and therapy resistance. We previously reported that high expression levels of the channel-kinase TRPM7, a protein that maintains the progenitor state of embryonic neural crest cells, are closely associated with progenitor-like features of tumor cells, accompanied by extensive cytoskeletal reorganization and adhesion remodeling. To define mechanisms by which TRPM7 may contribute to neuroblastoma progression, we applied a proteomics approach to identify TRPM7 interacting proteins. We show that TRPM7 is part of a large complex of proteins, many of which function in cytoskeletal organization, cell protrusion formation and adhesion dynamics. Expression of a subset of these TRPM7 interacting proteins strongly correlates with neuroblastoma progression in independent neuroblastoma patient datasets. Thus, TRPM7 is part of a large cytoskeletal complex that may affect the malignant potential of tumor cells by regulating actomyosin dynamics and cell-matrix interactions.
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Middelbeek
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Vrenken
authors.affiliation: Division of Cell Biology I, The Netherlands Cancer Institute (NKI-AVL), Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Daan
authors.initials: D
authors.lastname: Visser
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands; School of Biomedical & Healthcare Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Portland Square, Plymouth, PL4 8AA, UK.
authors.forename: Edwin
authors.initials: E
authors.lastname: Lasonder
authors.affiliation: Department of Oncogenomics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Division of Cell Biology I, The Netherlands Cancer Institute (NKI-AVL), Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Jalink
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands; Sygnature Discovery Limited, Biocity, Pennyfoot street, Nottingham, NG1 1GF, UK.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Clark
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Electronic address: FrankN.vanLeeuwen@radboudumc.nl.
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
mesh_terms: D000205:Actomyosin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D030541:Databases, Genetic; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D050053:TRPM Cation Channels; D000205:Actomyosin; C421903:Trpm7 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human
keywords: Cell adhesion; Cell protrusion; Cytoskeletal proteins; Neuroblastoma progression; TRPM7