The Role of Immature Tumor Subpopulations In Pediatric Rhabdomyosarcoma

未成熟肿瘤亚群在小儿横纹肌肉瘤中的作用

• 批准号: 10584592
• 负责人: Xiang Chen
• 金额: $ 40.8万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584592
• 关键词: Adult; Aftercare; Archives; Bar Codes; Bayesian Analysis; Biopsy; Biopsy Specimen; Cell Cycle; Cell Nucleus; Cell Survival; Cells; Characteristics; Child; Childhood; Childhood Rhabdomyosarcoma; Childhood Solid Neoplasm; Chromatin; Clinical; Collaborations; Computer Analysis; DNA Methylation; Data; Development; Diagnosis; Disease remission; Enhancers; Epigenetic Process; Evaluation; Ewings sarcoma; Formalin; Freezing; Gene Expression; Genes; Genetic Transcription; Genomics; Glioma; Goals; Government; Hematologic Neoplasms; Heterogeneity; Individual; Machine Learning; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mesoderm Cell; Methods; Modeling; Molecular; Monitor; Morphology; Muscle Cells; Myoblasts; Network-based; Normal Cell; Orthoptics; Outcome; Paraffin Embedding; Paraxial Mesoderm; Pathway interactions; Patients; Persons; Pilot Projects; Population; Positioning Attribute; Productivity; Rare Diseases; Recurrence; Recurrent disease; Recurrent tumor; Relapse; Research; Research Proposals; Resistance; Rhabdomyosarcoma; Risk; Risk Factors; Risk Reduction; Role; Saint Jude Children' s Research Hospital; Sampling; Skeletal Muscle; Solid; Specimen; Testing; Tissue-Specific Gene Expression; Translational Research; activity marker; anticancer research; biomarker development; chemotherapy; computerized tools; convolutional neural network; data mining; deep learning; disorder risk; epigenomics; experience; improved; improved outcome; in vivo; in vivo Model; innovation; leukemia; machine learning algorithm; methylation pattern; methylome; multidisciplinary; myogenesis; neoplastic cell; novel; patient derived xenograft model; preservation; prognostic significance; promoter; prototype; reconstitution; response; single nucleus RNA-sequencing; single-cell RNA sequencing; soft tissue; therapy resistant; transcriptome sequencing; transcriptomics; tumor; tumor DNA; tumor heterogeneity

PROJECT SUMMARY / ABSTRACT Rhabdomyosarcoma (RMS) is a devastating pediatric soft tissue cancer with morphological features of develop- ing skeletal muscles. Although most patients with RMS achieve a complete remission, one third will develop disease recurrence which is associated with a dismal clinical outcome. These clinical challenges underscore an urgent need to identify patients at risk for resistance and develop better therapy to reduce the risk of recurrence. Our pilot study revealed that rhabdomyosarcoma tumors have developmental intratumoral heterogeneity: differ- ent cells in a single tumor harbor transcriptomic feature of different myogenic stages. Moreover, tumor cells with developmentally immature characteristics are enriched in post-therapy specimens and have the potential to rep- licate and reconstitute the entire developmental trajectory after therapy. In this application, we will develop com- putational analysis methods to unambiguously identify immature tumor subpopulations in single cell RNA-seq data and to reveal their master deregulated genes (Aim 1); In Aim 2, we will characterize the changes in those transcriptional networks and cellular states during treatment in orthoptic patient derived xenograft models (O- PDXs) in vivo. And in Aim 3, we will develop an innovative deep-learning data mining approach to evaluate the prognostic significance of the myogenic transcriptional networks that underly RMS cellular heterogeneity in pa- tient tumors. The proposed study integrates computational, statistical and experimental approaches to study the role of immature cell populations in rhabdomyosarcoma recurrence. Building upon our computational expertise, research experience in rhabdomyosarcoma, robust preliminary results and highly productive collaborations with multi-disciplinary expertise in genomics/epigenomics, machine learning, Bayesian statistics and translational re- search in rhabdomyosarcoma, we are in a unique position to achieve the goals of this research proposal. The proposed research will be impactful because it will potentially change how we treat children with rhabdomyosar- coma and the developed computational/statistical approaches will be broadly applicable to cancer research.

项目概要/摘要 横纹肌肉瘤 (RMS) 是一种毁灭性的儿童软组织癌，其形态学特征为 ing 骨骼肌。尽管大多数 RMS 患者均获得完全缓解，但仍有三分之一的患者会出现症状 疾病复发与令人沮丧的临床结果相关。这些临床挑战强调了 迫切需要识别有耐药风险的患者并开发更好的治疗方法以降低复发风险。 我们的初步研究表明，横纹肌肉瘤肿瘤具有发育瘤内异质性： 单个肿瘤中的ent细胞具有不同肌生成阶段的转录组特征。此外，肿瘤细胞具有 发育不成熟的特征在治疗后的样本中得到丰富，并且有可能再现 复制并重建治疗后的整个发育轨迹。在此应用中，我们将开发com- 在单细胞 RNA-seq 中明确识别未成熟肿瘤亚群的推论分析方法 数据并揭示其主要的失调基因（目标 1）；在目标 2 中，我们将描述这些方面的变化 正交患者衍生异种移植模型（O- PDX）在体内。在目标 3 中，我们将开发一种创新的深度学习数据挖掘方法来评估 肌源转录网络的预后意义是 RMS 细胞异质性的基础 肿瘤。拟议的研究整合了计算、统计和实验方法来研究 未成熟细胞群在横纹肌肉瘤复发中的作用。基于我们的计算专业知识， 横纹肌肉瘤的研究经验、可靠的初步结果以及与 基因组学/表观基因组学、机器学习、贝叶斯统计和转化研究方面的多学科专业知识 在横纹肌肉瘤的研究中，我们处于独特的地位来实现本研究提案的目标。这 拟议的研究将会产生影响，因为它可能会改变我们治疗患有横纹肌肉瘤的儿童的方式 昏迷和开发的计算/统计方法将广泛适用于癌症研究。