Mapping the Cerebellar Origins of Medulloblastoma Subgroups

绘制髓母细胞瘤亚群的小脑起源图

• 批准号: 10587809
• 负责人: Paul Northcott
• 金额: $ 75.41万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-16 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587809
• 关键词: Acute; Affect; Area; Atlases; Automobile Driving; Biology; Brush Cell; Cells; Cerebellar Neoplasms; Cerebellum; Chemistry; Child; Childhood Cerebellar Neoplasm; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Consensus; Coupled; Credentialing; Data Set; Dependence; Development; Developmental Biology; Diagnosis; Disease; Disease model; Epigenetic Process; Exhibits; Fostering; Future; Generations; Genes; Genetic Transcription; Genomics; Glutamates; Human; Investigation; Knowledge; Lead; Life; Link; Lip structure; Literature; Longevity; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Molecular; Molecular Profiling; Mus; Mutation; Nature; Neuronal Differentiation; Oncogenic; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Population; Pre-Clinical Model; Proliferating; Quality of life; Regulator Genes; Relapse; Reporting; Research; Research Personnel; SHH gene; Science; Study models; Subgroup; Synthetic Genes; Testing; Therapeutic; Tumor Biology; Validation; biological heterogeneity; clinical heterogeneity; effective therapy; fetal; high risk; improved; improved outcome; innovation; insight; interdisciplinary approach; lens; medulloblastoma; medulloblastoma cell line; molecular targeted therapies; mortality; mouse model; multidisciplinary; new therapeutic target; next generation; novel; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; preclinical evaluation; progenitor; programs; protein degradation; scaffold; transcription factor; transcriptome; tumor; tumorigenesis

PROJECT SUMMARY Childhood cancers are the consequence of failed normal development. Medulloblastoma (MB), a malignant embryonal tumor of the cerebellum, exemplifies a highly aggressive pediatric cancer driven by aberrant activation of neurodevelopmental pathways and disruption of neuronal differentiation programs. Genomics has effectively divided MB into biologically and clinically distinct consensus molecular subgroups, including WNT, SHH, Group 3, and Group 4. Mouse tumor modeling studies have substantiated the cellular origins of WNT- and SHH-MB. In contrast, the developmental basis of Group 3/4-MB remains poorly understood, hampering context-relevant mechanistic studies, generation of accurate disease models, and the advancement of molecularly targeted therapies urgently needed to improve patient outcomes. Recent single-cell genomics studies lead by PI Northcott and others have provided initial clues into the putative origins of Group 4-MB, the largest and least characterized MB subgroup, implicating multiple glutamatergic lineages born out of the upper rhombic lip germinal zone. However, these studies failed to confidently identify cerebellar correlates of Group 3-MB, the most clinically challenging MB subgroup. Decoding the interplay between cellular lineages of the developing cerebellum and Group 3/4-MB pathogenesis represents a fundamental challenge in the field and will be the primary objective of this research program. We hypothesize that Group 3/4-MB tumors arise from discrete lineage trajectories during early cerebellar development. Solving the developmental origins of Group 3/4-MB will provide essential knowledge required to (i) investigate context-specific mechanisms of tumorigenesis; (ii) inform preclinical modeling strategies; (iii) identify previously hidden oncogenic drivers; and (iv) illuminate novel therapeutic opportunities. This hypothesis will be tested in three conceptually and technically innovative Specific Aims that integrate a multidisciplinary and multispecies experimental approach. In Aim #1, we will leverage an unprecedented single-cell transcriptional atlas of murine cerebellar development and elegant lineage enrichment strategies to enable cross-species inference of MB subgroup origins and execute context-relevant experimental perturbation of MB driver genes. In Aim #2, we will deliver the first comprehensive investigation of MB cellular origins through the lens of human fetal cerebellar development. These analyses will enlighten species-specific differences in cerebellar development linked to tumorigenesis and foster the discovery of tumor-specific signatures driving malignancy. In Aim #3, we will use focused CRISPR targeting, acute protein degradation, and next-generation synthetic gene regulators to define developmentally linked transcriptional dependencies in high- risk MB. These studies will credential conserved master transcription factors as attractive leads for future therapeutic consideration. Successful execution of this research program will fill an essential knowledge gap associated with the known biological and clinical heterogeneity of Group 3/4-MB and provide a novel direction for the pursuit of more specific, less toxic treatment options for affected children.

项目摘要 儿童癌症是正常发育失败的结果。髓母细胞瘤（MB），恶性 小脑的胚胎性肿瘤，证实了一种由异常激活驱动的高度侵袭性儿科癌症 神经发育途径和神经元分化程序的中断。基因组学有效地 将MB分为生物学和临床上不同的共有分子亚组，包括WNT、SHH、 3、第四组。小鼠肿瘤模型研究已经证实了WNT-和SHH-MB的细胞起源。在 相比之下，3/4-MB小组的发展基础仍然知之甚少，阻碍了与环境相关的工作 机制研究，准确的疾病模型的产生，以及分子靶向治疗的进展 迫切需要改善患者预后的治疗方法。PI Northcott领导的单细胞基因组学研究 和其他人已经提供了初步的线索，推定的起源组4-MB，最大的和最少的特点 MB亚群，暗示多个多个神经元谱系产生于上菱形唇生发带。 然而，这些研究未能确定小脑相关的3-MB组，最临床 挑战MB亚组。解码发育中的小脑细胞谱系之间的相互作用 组3/4-MB发病机制代表了该领域的基本挑战，并将成为本研究的主要目标。 这个研究项目。我们假设第3/4-MB组肿瘤是在肿瘤生长过程中从离散的谱系轨迹中产生的。 小脑早期发育解决3/4-MB组的发育起源将提供必要的 所需的知识（i）研究肿瘤发生的背景特异性机制;（ii）告知临床前 建模策略;（iii）识别先前隐藏的致癌驱动因素;以及（iv）阐明新的治疗方法。 机会这一假设将在三个概念上和技术上创新的具体目标中得到检验， 整合多学科和多物种实验方法。在目标1中，我们将利用 小鼠小脑发育和优雅谱系富集的前所未有的单细胞转录图谱 策略，使跨物种的MB亚组起源的推断和执行上下文相关的实验 MB驱动基因的扰动。在目标#2中，我们将首次对MB蜂窝网络进行全面调查， 起源于人类胎儿小脑发育的透镜。这些分析将启发物种特异性 小脑发育的差异与肿瘤发生有关，并促进了肿瘤特异性 导致恶性肿瘤的特征在目标3中，我们将使用集中的CRISPR靶向，急性蛋白质降解， 下一代合成基因调节剂，以确定高水平发育相关的转录依赖性， 风险MB。这些研究将证明保守的主转录因子作为未来有吸引力的线索 治疗考虑。这项研究计划的成功执行将填补一个重要的知识空白 与3/4-MB组的已知生物学和临床异质性相关，并提供了新的方向 为受影响的儿童寻求更具体、毒性更小的治疗选择。