Pischedda Francesca, Ghirelli Alessia, Tripathi Vasvi, Piccoli Giovanni
Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy.
Pharmaceutics. 2023 Sep 12;15(9):2307. doi: 10.3390/pharmaceutics15092307.
Neuroblastoma is among the most common childhood cancers. Neuroblastoma in advanced stages is one of the most intractable pediatric cancers, notwithstanding the recent therapeutic advances. ALK mutations are among the leading cause of hereditary neuroblastoma and account for more than 14% of the somatically acquired alterations. ALK kinase activity is currently one of the main targets for pharmacological strategies. However, evidence from ALK fusion-positive lung cancer studies has shown that resistance to ALK inhibition arises during the therapy, causing a relapse within several years. IgLONs are membrane-bound proteins involved in cell-to-cell adhesion. The expression of the IgLON family results altered in different cancers. We found that the IgLON member Negr1 is downregulated in neuroblastoma. The ectopic overexpression of Negr1 impairs neuroblastoma growth in vitro and in vivo. Negr1 exists as a GPI-anchored membrane-bound protein and as a soluble protein released upon metalloprotease cleavage. We generated and characterized a panel of Negr1-derived peptides. The treatment with Negr1 protein and derived peptides induce ALK downregulation and halt neuroblastoma progression in vitro and in vivo.
神经母细胞瘤是最常见的儿童癌症之一。尽管近年来治疗取得了进展，但晚期神经母细胞瘤仍是最难治疗的儿科癌症之一。ALK突变是遗传性神经母细胞瘤的主要原因之一，占体细胞获得性改变的14%以上。ALK激酶活性目前是药理学策略的主要靶点之一。然而，ALK融合阳性肺癌研究的证据表明，治疗期间会出现对ALK抑制的耐药性，导致几年内复发。IgLONs是参与细胞间粘附的膜结合蛋白。IgLON家族的表达在不同癌症中发生改变。我们发现IgLON成员Negr1在神经母细胞瘤中下调。Negr1的异位过表达在体外和体内均损害神经母细胞瘤的生长。Negr1以糖基磷脂酰肌醇（GPI）锚定的膜结合蛋白形式存在，并以金属蛋白酶切割后释放的可溶性蛋白形式存在。我们生成并表征了一组Negr1衍生肽。用Negr1蛋白和衍生肽治疗可诱导ALK下调，并在体外和体内阻止神经母细胞瘤进展。
