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.

中文翻译：

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TRPM7相互作用基因组定义了与神经母细胞瘤进展相关的细胞骨架复合物。

神经母细胞瘤是儿童中第二常见的实体瘤，起源于分化差的神经c来源的祖细胞。尽管大多数晚期转移性神经母细胞瘤患者最初对治疗有反应，但经常会出现耐药性低分化细胞库，从而导致难治性疾病。缺乏对神经母细胞瘤发展的分子机制的认识，阻碍了这些患者有效新疗法的发展。正常的神经rest发育和成熟除了细胞生长因子等可溶性因子外，还受到细胞与其周围环境之间的物理相互作用的指导。这种机械性串扰是由基于肌动蛋白的粘附结构和细胞突起介导的，这些结构和突起探测细胞环境以调节迁移，增殖，生存和分化。此类信号可保持非恶性细胞中的细胞静止，而受干扰的粘附信号可促进去分化，不受控制的细胞增殖，组织浸润和治疗抗性。我们以前曾报道过，通道激酶TRPM7（一种维持胚胎神经c细胞的祖细胞状态的蛋白）的高表达水平与肿瘤细胞的祖细胞样特征密切相关，并伴随着广泛的细胞骨架重组和粘附重塑。为了定义TRPM7可能有助于神经母细胞瘤进展的机制，我们应用了蛋白质组学方法来鉴定TRPM7相互作用蛋白。我们表明TRPM7是蛋白质的大复合体的一部分，其中许多在细胞骨架组织，细胞突起形成和粘附动力学中起作用。在独立的神经母细胞瘤患者数据集中，这些TRPM7相互作用蛋白的子集的表达与神经母细胞瘤的进展密切相关。因此，TRPM7是大型细胞骨架复合物的一部分，该复合物可能通过调节肌动球蛋白的动力学和细胞-基质相互作用来影响肿瘤细胞的恶性潜能。