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Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma

Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma
小儿横纹肌肉瘤分化停滞的介质
批准号:
10559589
负责人:
Mark Edward Hatley
金额:
$40.24万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-02-01 至 2026-01-31

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中文摘要
翻译
项目摘要/摘要 横纹肌肉瘤(RMS)是儿童最常见的软组织肉瘤。尽管进行了严格的临床试验 患有高危RMS的儿童的存活率三十年来没有改变。幸存下来的孩子们 由于积极的治疗,经常遭受终身毁容。RMS被细分为两个 主要类别,融合阳性(FP-RMS)和融合阴性(FN-RMS),基于是否存在 PAX3-FOXO1或PAX7-FOXO1基因融合。RMS类似于发育中的骨骼肌,一直以来 推测其起源于基因受损的骨骼肌祖细胞。尽管表达了 骨骼肌主调节蛋白MYOD1和MYOGENIN、RMS肿瘤和细胞未能末端 分化,表明RMS是肌肉发育的停滞状态。基因工程的分子基础 RMS的分化停滞和促进分化的治疗方法尚不清楚。长期目标是 阐明决定RMS发育停滞基础的机制,并设计新的、定向的 治疗RMS的药物疗法。最近的一项研究发现PTEN启动子高甲基化伴随PTEN的降低 在90%以上的FN-RMS肿瘤中均有表达。在RMS转基因小鼠模型(GEMM)中,PTEN缺失 肿瘤潜伏期缩短,肿瘤外显率增加,分化程度低得多的肿瘤更接近 类似于儿童的胚胎RMS。PTEN缺失不会增加mTOR信号转导,但定位于 核内PAX7表达增加,Dbx1异位表达增加。DBX1是一种神经元特异性的 转录抑制因子在人类FN-RMS和FP-RMS中异位表达。强制Dbx1 在培养的成肌细胞中,表达抑制成肌细胞分化。中心假设是PTEN-PAX7- Dbx1轴在RMS的发育停滞中提供了一个关键节点,并且Dbx1作为转录因子发挥作用 抑制因子阻断RMS的分化。这项提议的目标是利用我们健壮的RMS鼠标 结合体外实验确定PTEN和Dbx1在RMS中的作用。为了实现这一目标, 我们提出了以下具体目标:1)明确PTEN缺失在RMS中的作用。2)确定机制 Dbx1调控在RMS中的表达。3)明确Dbx1在阻断RMS肌源性分化中的作用。建议数 研究利用简单、快速的RMS GEMM在体内剖析有助于RMS生物学的基因并提供 深入了解RMS中维持分化停滞状态的机制。我们将用得和失- 体内和体外研究AKT1、mTORC1、PAX7和Dbx1的功能 PTEN缺失表型的调控。胚胎肿瘤的分化治疗已被证明是有效的 13-顺式维甲酸治疗神经母细胞瘤,全反式维甲酸治疗急性早幼粒细胞白血病 白血病。RMS的分子和发育解剖将揭示新的漏洞以开发新的 治疗手段推动RMS的终末分化。这些研究将产生广泛的影响,因为Dbx1 在儿童脑肿瘤中表达,PTEN基因的紊乱参与了许多癌症的发生。
英文摘要
Project Summary/Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Despite rigorous clinical trials the survival for children with high-risk RMS has not changed for three decades. The children that do survive often suffer from life-long disfigurements as a result of the aggressive treatment. RMS is subdivided into two major classes, fusion-positive (FP-RMS) and fusion-negative (FN-RMS), based on the presence or absence of the PAX3-FOXO1 or PAX7-FOXO1 gene fusions. RMS resembles developing skeletal muscle and has been speculated to originate from genetically compromised skeletal muscle progenitors. Despite the expression of skeletal muscle master regulator proteins MYOD1 and MYOGENIN, RMS tumors and cells fail to terminally differentiate, suggesting that RMS is an arrested state of muscle development. The molecular underpinnings of the differentiation arrest in RMS and therapeutics to drive differentiation are unknown. The long-term goal is to elucidate the mechanisms that determine the basis for developmental arrest in RMS and design novel, directed drug therapies for RMS. A study recently identified PTEN promoter hypermethylation with decrease PTEN expression in over 90% of FN-RMS tumors. In a RMS genetically engineered mouse model (GEMM), PTEN loss decreased tumor latency, increased tumor penetrance, and much less differentiated tumors more closely resembling the embryonal RMS in children. PTEN loss did not increase mTOR signaling but was localized in the nucleus and increased PAX7 expression and ectopic DBX1 expression. DBX1 is a neuronal specific transcriptional repressor that is ectopically expressed across both human FN-RMS and FP-RMS. Forced DBX1 expression blocks myogenic differentiation in cultured myoblasts. The central hypothesis is that the PTEN-PAX7- DBX1 axis provides a key node in the developmental arrest in RMS and that DBX1 functions as a transcriptional repressor blocking differentiation in RMS. The objective of this proposal is to leverage our robust RMS mouse models coupled with in vitro assays to define the role of PTEN and DBX1 in RMS. To accomplish this objective, we propose the following Specific Aims: 1) Define the role of PTEN loss in RMS. 2) Determine the mechanism of DBX1 regulation in RMS. 3) Identify role of DBX1 in blocking myogenic differentiation in RMS. The proposed studies leverage a simple, rapid RMS GEMM to dissect genes that contribute to RMS biology in vivo and provide insight into the mechanism maintaining an arrested state of differentiation in RMS. We will use gain- and loss- of-function approaches both in vivo and in vitro to dissect the roles of AKT1, mTORC1, PAX7 and DBX1 in modulation of the PTEN loss phenotype. Differentiation therapy of embryonal tumors has proven an efficacious venue for therapy with 13-cis-retinoic acid for neuroblastoma and all-trans-retinoic acid for acute promyelocytic leukemia. Molecular and developmental dissection of RMS will reveal new vulnerabilities to develop new therapeutics to drive terminal differentiation of RMS. These studies will have broad impact as DBX1 is highly expressed in pediatric brain tumors and PTEN perturbations are involved in many cancers.
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Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma
Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma
Defining the non-myogenic origins of pediatric rhabdomyosarcoma
Defining the non-myogenic origins of pediatric rhabdomyosarcoma
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