Deciphering heritability, plasticity and differentiation trajectories in gliomas via single-cell multi-omics

通过单细胞多组学解读神经胶质瘤的遗传性、可塑性和分化轨迹

• 批准号: 10614478
• 负责人: Mario Luca Suva
• 金额: $ 54.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614478
• 关键词: Address; Automobile Driving; Biological Assay; Biology; CDK4 gene; Cancer Model; Cell Differentiation process; Cells; Chromatin; Clinical; Clonal Evolution; Computer Analysis; Computing Methodologies; Coupled; DNA; DNA Methylation; Data; Data Set; Development; Diffuse; Disease; Epidermal Growth Factor Receptor; Epigenetic Process; Evolution; Gene Expression Profile; General Hospitals; Genetic; Genetic Transcription; Genetic Variation; Genome; Genotype; Glioblastoma; Glioma; Grant; Growth; Hematologic Neoplasms; Heritability; Human; Joints; Knock-out; Laboratories; Ligands; Link; MDM2 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Massachusetts; Measures; Medicine; Methods; Modality; Mutation; New York; PDGFRA gene; PIK3CA gene; Phenotype; Phylogenetic Analysis; Recording of previous events; Recurrence; Research Proposals; Resolution; Role; Sampling; Somatic Mutation; Source; Specimen; Systems Biology; Technology; Testing; Trees; Variant; cancer cell; candidate validation; cell dimension; driver mutation; effective therapy; experimental study; fitness; genetic information; in vivo; methylome; model organism; multimodality; multiple omics; mutant; neoplastic cell; novel; novel therapeutics; programs; receptor; sequencing platform; single cell sequencing; single-cell RNA sequencing; stem cells; therapy resistant; transcription factor; transcriptome; tumor

Abstract Cancer evolution constitutes a foremost obstacle to effective treatment, driving malignant cells to adapt and overcome therapy. Diffuse glioma illustrates the quandary of cancer evolution: despite maximal treatment, the disease invariably recurs. Recent single-cell RNA-sequencing (scRNAseq) profiling of gliomas in the Suvà laboratory showed that defined cellular states, developmental hierarchies and plasticity coordinate to fuel glioma growth, evolution and resistance to therapy. However, this raises the critical question of the determinants of glioma cell states. We hypothesize that genetic, epigenetic and micro-environmental determinants govern the biology of key cellular states that drive gliomas and their plasticity, calling for an integrative model of cancer evolution, encompassing all sources of intra-tumoral heritable variations. To address this challenge, the Landau laboratory developed novel multi-modality single-cell sequencing technologies that enable direct integration across genetic, epigenetic, and transcriptional dimensions of cell-to-cell variation, and have applied them to study clonal evolution in hematological malignancies. In this R01 co-PI collaborative grant, we seek to apply this multi-layered single-cell approach to human gliomas in order to define how cellular phenotypic plasticity and clonal evolution enable tumor cell fitness. Specifically, we will: define intrinsic and extrinsic determinants of cellular states in glioma (aim1), map the epigenetic encoding of cell state programs in glioma (aim2), and reconstruct high-resolution lineage histories of glioma single-cells to measure the heritability and plasticity of cell states (aim3). Altogether, this research proposal seeks to pioneer the integrative analysis of epigenetic identity with genetic and transcriptional information to systematically dissect drivers of cellular states that underlie glioma differentiation and evolution.

摘要