Defective Myoblast Fusion Signaling in Rhabdomyosarcoma Pathogenesis

 描述(申请人提供)：横纹肌肉瘤(RMS)是最常见的儿童软组织肉瘤，是一种肌肉系成肌细胞的恶性肿瘤，阻止其分化为合体肌肉。RMS通常分为两个亚型：胚胎型RMS(E-RMS)和肺泡型RMS(A-RMS)，前者更为常见，后者更具侵袭性。尽管进行了密集的治疗，患有高危RMS的儿童3年无事件存活率只有20%。30年来，对高危RMS的治疗一直没有改善，这突显了阐明这种疾病的分子基础和设计新的精确药物疗法的必要性。使用创新的果蝇RMS相关模型，实验室进行了无偏见的遗传修饰物筛选，以揭示RMS的新遗传驱动因素。将这些发现扩展到哺乳动物系统，我们最近报道了TANC1的错误表达，它编码了一种调节成肌细胞细胞-细胞融合的适配器分子，失调了融合信号并促进了RMS。由于哺乳动物成肌细胞融合所需的机制在很大程度上尚未被探索，因此，调控失调的成肌细胞融合驱动RMS的概念是新的。1)免疫球蛋白超家族(Ig-S)跨膜受体(Ig-S-R)家族成员Kirrel和Neferin是可能的融合调节因子，其在RMS中的表达可能发生改变。柯雷尔或内弗林在RMS中的角色尚未被探索。2)EGFR信号在果蝇成肌细胞分化和融合中起关键作用，而EGFR在 哺乳动物成肌细胞融合/成熟或RMS的功能尚未被探索。我们的初步数据现在认为，EGFR的过度表达错误地调控了驱动RMS的成肌细胞融合机制。我们还表明，沉默或药物抑制的EGFR在体内拮抗RMS肿瘤的发生。研究结果表明，EGFR过度表达是一种具有刺激性和靶向性的RMS发病机制。在这个方案中，我们的目标是：1)确定在RMS中激发缺陷成肌细胞融合潜能的关键跨膜受体；2)测试EGFR信号是否支持RMS分化-阻止；以及3)询问TANC1、KIRREL和NEPHRIN以及EGFR在人类肿瘤中的表达。我们的总体目标是使用我们的信息性和互补性模型系统来揭示RMS背后的新机制。我们的长期目标是将这些见解转化为新的定向RMS疗法。我们推测，我们的创新策略将为RMS精确治疗揭示新的分子靶点，从而对RMS的发病率和死亡率产生积极的临床影响。

 DESCRIPTION (provided by applicant): Rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, is a malignancy of muscle-lineage myoblasts that are blocked from differentiating into syncytial muscle. RMS is typically divided into two subgroups: Embryonal RMS (E-RMS), which is more common, and Alveolar RMS (A-RMS), which is more aggressive. Despite intensive therapy, children with high-risk RMS suffer from a 3-year event-free survival of only 20%. Treatments for high-risk RMS have not improved for three decades, underscoring the need to elucidate the molecular underpinnings of the disease and design new precision drug therapies. Using an innovative Drosophila RMS-related model, the lab conducted an unbiased genetic modifier screen to uncover new genetic drives of RMS. Extending these findings to mammalian systems, we recently reported that misexpression of TANC1, which encodes an adaptor molecule that regulates myoblast cell-cell fusion, dysregulates fusion signaling and promotes RMS. As the machinery necessary for mammalian myoblast fusion is largely unexplored, the notion that dysregulated myoblast fusion drives RMS was novel. Since our the discovery of dysregulated myoblast fusion in RMS, we have explored/learned the following: 1) The Immunoglobulin Superfamily (Ig-S) transmembrane Receptor (Ig-S-R) family members Kirrel and Nephrin are putative fusion regulators, expression of which appears altered in RMS. Roles for Kirrel or Nephrin in RMS have not been explored. 2) EGFR signaling is critical in flies for myoblast differentiation and fusion, yet a role for EGFR in mammalian myoblast fusion/maturation or RMS has not been functionally explored. We preliminary data now argue that EGFR overexpression misregulated the myoblast fusion machinery, which drives RMS. We have also shown the silencing or pharmacologic inhibition of EGFR antagonizes RMS tumorigenesis in vivo. The findings argue that EGFR overexpression is a provocative and targetable RMS pathogenesis mechanism. In this proposal, we aim to: 1) Identify the key transmembrane receptors that incite defective myoblast fusion potential in RMS; 2) Test whether EGFR signaling underlies RMS differentiation-arrest; & 3) Interrogate expression of TANC1, KIRREL and NEPHRIN, and EGFR in human tumors. Our overall objective is to use our informative and complementary model systems to uncover new mechanisms underlying RMS. Our long-term goal is to translate these insights into new directed RMS therapies. We postulate that our innovative strategies will reveal new molecular targets for RMS precision therapy and therein have a positive clinical impact on RMS morbidity and mortality.