Cytokine- and Satellite Cell-mediated Muscle Disease Promotion

 描述（由申请人提供）：肌肉变性/再生的重复循环可加剧肌肉萎缩症和肌肉减少症等疾病中的组织衰退。这种下降可以通过涉及选择的细胞因子和/或肌肉干细胞（即，卫星细胞（SC）。横纹肌肉瘤（RMS）是一种高度转移且通常致命的儿童软组织肉瘤，肿瘤通常发生在肌肉中，并显示出肌肉再生部位更常见的慢性损伤的组织病理学特征。基于这些观察结果和我们最近发表的研究结果，SC的慢性激活被认为在促进RMS的肿瘤进展中发挥了功能性作用。我们的实验数据包括：（i）SC以白细胞介素（IL）-4受体（IL 4 R β）依赖性方式促进肿瘤植入，（ii）IL 4 R β阻断显著减少淋巴和血行转移，以及（iii）SC与RMS细胞的融合也是IL 4 R β依赖性的，其功能意义尚不清楚。也就是说，关于后者，鼠RMS模型中的融合细胞强烈地让人联想到在人RMS中发现的多核、分化但增殖的（Ki 67+）横纹肌母细胞。鉴于类似的多核细胞在其他形式的肉瘤中也是肿瘤增殖的，我们假设IL 4 R β阻断将通过干扰RMS-SC相互作用来防止新的RMS植入、转移和复发，因此代表了儿童RMS的有效治疗策略。为了应对患有这种疾病的儿童对新药物的迫切临床需求，我们的总体目标不仅是确定调节RMS进展的功能性重要机制，而且还将这些知识转化为与儿童肿瘤组合作试验研究者合作的RMS干预的可行治疗策略。因此，采用最先进的遗传小鼠RMS模型和人RMS培养模型，采用组合的肌肉和肿瘤生物学方法，我们将：（目的1）描述SC-肿瘤细胞融合对RMS进展的贡献，并揭示IL 4 R趋化性以及CCL-CCR趋化性对细胞融合的功能意义。这些研究将确定实验产生的多核SC-RMS融合细胞的致瘤特性（植入、转移、化疗-辐射抗性）。(Aim 2）我们将确定浸润宿主细胞、SC和恶性RMS细胞中IL 4 R β信号传导对疾病进展的功能贡献。这些遗传学研究将定义RMS肿瘤微环境中SC、RMS细胞和基质细胞（巨噬细胞、成纤维细胞、纤维细胞-脂肪细胞祖细胞）中IL 4 R β信号传导的意义，和（目的3）。我们将使用临床级试剂，例如，REGN668。最后，这些研究的结果将确定由IL 4 Ra信号调节的功能机制是RMS，可以快速转化为临床。

 DESCRIPTION (provided by applicant): Repeated cycles of muscle degeneration/regeneration can exacerbate tissue decline in conditions such as muscular dystrophy and sarcopenia. This decline can occur via molecular/cellular processes involving select cytokines and/or muscle stem cells (i.e., satellite cells, SCs). In rhabdomyosarcoma (RMS), a highly metastatic and often deadly soft tissue childhood sarcoma, tumors typically arise in muscle and show histopathological features of chronic damage more common to sites of muscle regeneration. Based on these observations and our recently published findings, chronic activation of SCs is implicated as playing a functional role in fostering neoplastic progression of RMS. Our experimental data include that: (i) SCs facilitate tumor engraftment in an interleukin (IL)-4 Receptor (IL4R)-dependent manner, (ii) IL4R-blockade significantly curtails lymphatic and hematogenous metastases, and (iii) SCs fusion to RMS cells is also IL4R-dependent, the functional significance of which is yet unknown. That said, with regard to the latter, fused cells in murine RMS models are strongly reminiscent of multinucleated, differentiated yet proliferative (Ki67+) rhabdomyoblasts found in human RMS. Given that similar multinucleated cells are tumor-propagating in other forms of sarcoma, we hypothesize that IL4R blockade will prevent new RMS engraftment, metastases and relapse by interfering with RMS-SC interactions and thus represent an efficacious therapeutic strategy for children with RMS. In response to the pressing clinical need of children with this disease for new agents, our overall goal here is not only to identify functionally significant mechanisms regulating RMS progression, but to also translate this knowledge into a feasible therapeutic strategy for RMS intervention in partnership with Children's Oncology Group cooperative trial investigators. Thus, taking a combined muscle and tumor biology approach using state-of-the-art genetic murine RMS models and human RMS culture models, we will: (Aim 1) Delineate contribution of SC-tumor cell fusion to RMS progression, and reveal functional significance of IL4R as well as CCL-CCR chemotaxis for cell fusion. These studies will define tumorigenic properties (engraftment, metastasis, chemotherapy-radiation resistance) of experimentally-generated, multinucleated SC-RMS fused cells. (Aim 2) We will determine the functional contribution of IL4R signaling in infiltrating host cells, SCs and malignant RMS cells to disease progression. These genetic studies will define significance of IL4R signaling in SCs, RMS cells, and stromal cells (macrophages, fibroblasts, fibrocyte- adipocyte progenitors) in the RMS tumor microenvironment, and (Aim 3). We will evaluate the IL4R signaling cascade as a preclinical therapeutic target in RMS with a clinical-grade reagent, e.g., REGN668. In the end, results from these studies will define functional mechanisms regulated by IL4Ra signaling is RMS that can be rapidly translated to the clinic.