Cytokine- and Satellite Cell-mediated Muscle Disease Promotion

细胞因子和卫星细胞介导的肌肉疾病促进

基本信息

批准号：
9319227
负责人：
CHARLES KELLER
金额：
$ 33.79万
依托单位：
CHILDREN'S CANCER THERAPY DEVELOP/INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-11 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319227
关键词：
Adipocytes Allografting Alveolar Rhabdomyosarcoma Anatomy Attenuated Blocking Antibodies Blood Vessels CCR Cachexia Cell Communication Cell Survival Cell fusion Cell hybridization Cell physiology Cells Chemotaxis Child Childhood Childhood Soft Tissue Sarcoma Chronic Clinic Clinical Data Disease Disease Progression Embryonal Rhabdomyosarcoma Engraftment Fc Receptor Fibroblasts Fostering Genetic Genetic study Goals Hematogenous Human Human Cell Line Hybrid Cells Interleukin 4 Receptor Interleukin-4 Intervention Knowledge Leukocytes Lymphatic Malignant - descriptor Mammary Neoplasms Mediating Modeling Molecular Mus Muscle Muscle Development Muscle satellite cell Muscular Dystrophies Myomatous neoplasm Myopathy Natural regeneration Neoplasm Metastasis New Agents Non-Malignant Outcome Paracrine Communication Patients Pediatric Oncology Group Phase I/II Trial Play Process Property Publishing Quality of life Radiation Reagent Receptor Gene Receptor Signaling Relapse Research Personnel Resistance Rhabdomyoblast Rhabdomyosarcoma Role SCID Mice Signal Transduction Site Solid Neoplasm Source Stromal Cells System Testing Therapeutic Tissues Translating Tumor Biology Tumorigenicity base chemotherapy chronic wound cytokine genetic approach improved improved outcome in vivo macrophage malignant muscle neoplasm muscle degeneration muscle regeneration neoplastic cell neutralizing antibody null mutation pre-clinical preclinical study prevent progenitor public health relevance radiation resistance receptor repaired response sarcoma sarcopenia satellite cell targeted treatment therapeutic target tool tumor tumor microenvironment tumor progression tumorigenic wound

项目摘要

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.

描述（由申请人提供）：肌肉退化/再生的重复循环会加剧肌营养不良和肌肉减少症等疾病的组织衰退，这种衰退可能通过涉及选定细胞因子和/或肌肉干细胞（即卫星细胞）的分子/细胞过程发生。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，肿瘤通常出现在肌肉中，并表现出更常见的慢性损伤的组织病理学特征。根据这些观察结果和我们最近发表的研究结果，SCs 的慢性激活在促进 RMS 肿瘤进展中发挥着功能性作用，我们的实验数据包括：（i）SCs 促进白细胞介素中的肿瘤植入。 (IL)-4 受体 (IL4Rα) 依赖性方式，(ii) IL4Rα 阻断显着减少淋巴和血行转移，以及 (iii) SC与 RMS 细胞融合的细胞也是 IL4Rα 依赖性的，其功能意义尚不清楚。也就是说，对于后者，小鼠 RMS 模型中的融合细胞很容易让人联想到在体内发现的多核、分化但增殖的横纹肌细胞。鉴于类似的多核细胞在其他形式的肉瘤中也能进行肿瘤增殖，我们利用 IL4R 阻断来阻止新的肿瘤增殖。通过干扰 RMS-SC 相互作用来实现 RMS 植入、转移和复发，因此代表了 RMS 儿童的有效治疗策略。为了满足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仅是确定。与儿童肿瘤学小组合作试验研究人员合作，将这些知识转化为 RMS 干预的可行治疗策略，因此，采用肌肉和肿瘤生物学相结合的方法。通过最先进的遗传小鼠 RMS 模型和人类 RMS 培养模型，我们将：（目标 1）描绘 SC 肿瘤细胞融合对 RMS 进展的贡献，并揭示 IL4Rα 以及 CCL-CCR 趋化性的功能意义这些研究将定义实验产生的多核 SC-RMS 融合细胞的致瘤特性（植入、转移、化疗放射抗性）。（目标 2）我们将确定 IL4Rα 信号在浸润性宿主细胞、SC 和恶性 RMS 细胞中对疾病进展的功能贡献。这些遗传学研究将确定 IL4Rα 信号在 SC、RMS 细胞和基质细胞（巨噬细胞、巨噬细胞、间质细胞）中的重要性。 RMS 肿瘤微环境中的成纤维细胞、纤维细胞-脂肪细胞祖细胞），以及（目标 3）。使用临床级试剂（例如 REGN668）将信号级联作为 RMS 的临床前治疗靶标。最终，这些研究的结果将定义 RMS 受 IL4Ra 信号调节的功能机制，可以快速转化为临床。