Karki Anju, Purohit Reshma, Nosack Sofia, Bharathy Narendra, Michalek Joel E, Chen Sonja, Keller Charles
Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Sarcoma. 2022 May 6;2022:9646909. doi: 10.1155/2022/9646909. eCollection 2022.
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma for which subsets of patients have longstanding unmet clinical needs. For example, children with alveolar rhabdomyosarcoma and metastases at diagnosis will experience only 8% disease-free 5-year survival for nonlocalized unresectable recurrent disease. Hence, development of novel therapeutic strategies is urgently needed to improve outcomes. The Plexin-Semaphorin pathway is largely unexplored for sarcoma research. However, emerging interest in the Plexin-Semaphorin signaling axis in pediatric sarcomas has led to phase I cooperative group dose-finding clinical trials, now completed (NCT03320330). In this study, we specifically investigated the protein expression of transmembrane receptor Plexin-B2 and its cognate SEMA4C ligands in clinical RMS tumors and cell models. By RNA interferences, we assessed the role of Plexin-B2 in cell growth and cell migration ability in selected alveolar and embryonal RMS cell model systems. Our results affirmed expression of Plexin-B2 across human samples, while also dissecting expression of the different protein subunits of Plexin-B2 along with the assessment of preferred Semaphorin ligands of Plexin-B2. Plexin-B2 knockdown had positive or negative effects on cell growth, which varied by cell model system. Migration assayed after Plexin-B2 knockdown revealed selective cell line specific migration inhibition, which was independent of Plexin-B2 expression level. Overall, these findings are suggestive of context-specific and possibly patient-specific (stochastic) role of Plexin-B2 and SEMA4 ligands in RMS.
横纹肌肉瘤（RMS）是最常见的小儿软组织肉瘤，部分患者长期存在未满足的临床需求。例如，诊断时患有肺泡型横纹肌肉瘤并伴有转移的儿童，对于非局限性不可切除的复发性疾病，其5年无病生存率仅为8%。因此，迫切需要开发新的治疗策略来改善治疗效果。在肉瘤研究中，丛状蛋白-信号素通路在很大程度上尚未得到充分探索。然而，小儿肉瘤中对丛状蛋白-信号素信号轴的兴趣日益浓厚，已开展了I期协作组剂量探索性临床试验，目前已完成（NCT03320330）。在本研究中，我们专门研究了跨膜受体丛状蛋白-B2及其同源信号素4C配体在临床RMS肿瘤和细胞模型中的蛋白表达。通过RNA干扰技术，我们评估了丛状蛋白-B2在选定的肺泡型和胚胎型RMS细胞模型系统中对细胞生长和细胞迁移能力的作用。我们的结果证实了丛状蛋白-B2在人类样本中的表达，同时还剖析了丛状蛋白-B2不同蛋白亚基的表达情况，并评估了丛状蛋白-B2的首选信号素配体。丛状蛋白-B2基因敲低对细胞生长有正向或负向影响，这因细胞模型系统而异。丛状蛋白-B2基因敲低后进行的迁移分析显示，存在选择性的细胞系特异性迁移抑制，这与丛状蛋白-B2的表达水平无关。总体而言，这些发现提示丛状蛋白-B2和信号素4配体在RMS中具有背景特异性以及可能的患者特异性（随机）作用。
