Unbiased identification of spliceosome vulnerabilities across cancer

公正地鉴定癌症中剪接体的脆弱性

• 批准号: 10194414
• 负责人: Nathan G. Salomonis
• 金额: $ 41.69万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194414
• 关键词: Abnormal Karyotype; Acute Myelocytic Leukemia; Adult; Alternative Splicing; Apoptotic; Binding; Binding Sites; Biological Markers; Cause of Death; Child; Childhood Acute Myeloid Leukemia; Communities; Computing Methodologies; Data; Data Set; Detection; Development; Disease; Elements; Evaluation; Event; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Rearrangement; Genetic; Genetic Transcription; Growth; Hematologic Neoplasms; Human; Immune; Learning; Libraries; Link; MYC gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Messenger RNA; Methods; Methylation; Modeling; Mutation; Neoplasm Metastasis; Normal Cell; Oncogenes; Oncogenic; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphotransferases; Prognosis; Protein Isoforms; Proteins; Proteomics; RNA; RNA Splicing; Recurrence; Recurrent Malignant Neoplasm; Regulatory Pathway; Reproducibility; Research Personnel; Role; SRSF2 gene; Sampling; Series; Signal Transduction; Solid Neoplasm; Spliced Genes; Spliceosomes; Supervision; TP53 gene; Techniques; Testing; Therapeutic; Validation; Work; cancer genomics; cancer subtypes; design; driver mutation; experimental study; genetic variant; genomic variation; improved; innovation; insight; multiple omics; neoplasm resource; new therapeutic target; novel; novel therapeutic intervention; overexpression; programs; tool; transcriptome; tumor

PROJECT SUMMARY: Although alternative splicing is one of the major drivers of cellular diversity and growth during development, the splicing machinery can be hijacked in cancer to promote metastasis, immune escape, invasion and anti- apoptotic actions. While splicing factor mutations occur in 1-15% of patients, depending on the cancer, emerging data suggest that commonly dysregulated oncogenes such as MYC indirectly regulate mRNA processing pathways leading to cancer promoting alternative splice isoforms in distinct malignancies. Using a series of recently developed unsupervised splicing detection and candidate splicing regulatory prediction techniques, we discovered that splicing is broadly disrupted in adult and pediatric cancers independent of obvious splicing factor mutations. These data suggest a potentially paradigm shifting model, in which widespread coordinated splicing dysfunction occurs across cancers, likely via imbalances in splicing factor expression, signaling or genetic alternations. If true, spliceosome directed and upstream therapies may be broadly repurposed across cancers, focused on specific splicing signatures and implicated regulatory pathways rather than on specific mutations alone. To test these hypotheses and develop reusable analytical resources for the cancer community, we propose the following aims. Aim 1: Implicate key splicing pathway vulnerabilities with observed oncogenic events across diverse cancers. We will characterize alternative splicing on a global-level with our existing integrative multi- omics computational workflow across dozens of cancers and thousands of samples. Splicing events identified using novel unsupervised or supervised analyses will be compared within and between distinct cancers as well as normal cells of different origins to define reproducible tumor intrinsic vs. differentiation associated programs. Aim 2: Define and validate the core splicing regulatory networks in pediatric AML and diverse human cancers. We will build and validate a novel learning model to define the splicing regulatory network in pediatric AML and ultimately across diverse adult and pediatric cancers. We will adapt current best practices for multi-evidence transcriptional regulatory network inference to splicing and rigorously test our models with validation data. A large library of experimental splicing factor binding datasets will be used to improve our predictions. These analyses will identify novel splicing regulators and RNA recognition elements. Aim 3: Build a discovery platform for precision splicing biomarker detection and selective splicing target inhibition. We will develop an interactive computational interface to identify specific RNA isoforms associated with poor prognosis splicing subtypes in diverse cancers obtained in Aim 1. By integrating splicing, gene expression, proteomics and methylation data on the same patients, we will enable the discovery of splicing events linked to diverse modes of gene regulation, that potentially manifest at the protein level. Associated isoform interactions and weighted coexpression networks will be built to prioritize specific splicing events in known cancer pathways.

项目摘要： 尽管替代剪接是发育过程中细胞多样性和生长的主要驱动因素之一，但 可以将剪接机械劫持在癌症中，以促进转移，免疫逃生，入侵和抗 - 凋亡动作。尽管剪接因子突变发生在1-15％的患者中，但取决于癌症，但 新兴的数据表明，通常失调的癌基因（例如MYC）间接调节mRNA 加工途径导致癌症促进不同恶性肿瘤的替代剪接同工型。使用 一系列最近开发的无监督剪接检测和候选剪接调节预测 技术，我们发现与独立于成人和儿科癌症中的剪接受到了广泛的破坏 明显的剪接因子突变。这些数据表明一个潜在的范式转移模型，其中 广泛协调的剪接功能障碍发生在癌症之间，可能是由于剪接因子的失衡而发生的 表达，信号传导或遗传交替。如果是真的，则指导和上游疗法的剪接体可能是 跨癌症广泛重新使用，重点是特定的剪接特征，并涉及监管 途径而不是仅在特定突变上。测试这些假设并发展可重复使用的分析 为癌症界的资源，我们提出以下目标。 目标1：暗示关键的剪接途径脆弱性与观察到的肿瘤事件 多样化的癌症。我们将以我们现有的集成多种方式来表征全球层面上的替代拼接 数十个癌症和成千上万样品的OMICS计算工作流程。确定的剪接事件 还将比较不同的无监督或监督分析，也将在不同的癌症之间进行比较 作为不同起源的正常细胞，可以定义可重复的肿瘤固有和相关程序。 目标2：定义和验证小儿AML中的核心剪接调节网络 人类癌。我们将构建和验证一种新颖的学习模型，以定义拼接调节网络 小儿AML，最终遍及多样化的成人和儿科癌症。我们将适应当前的最佳实践 用于多个证据转录调节网络推断，以拼接并严格测试我们的模型 验证数据。大量的实验剪接因子绑定数据集将用于改善我们的 预测。这些分析将确定新颖的剪接调节剂和RNA识别元件。 AIM 3：建立一个发现平台，用于精确剪接生物标志物检测和选择性剪接 目标抑制。我们将开发一个交互式计算接口，以识别特定的RNA同工型 与在AIM 1中获得的各种癌症中预后剪接亚型不良相关。通过整合剪接， 同一患者的基因表达，蛋白质组学和甲基化数据，我们将能够发现 与基因调节模式相关的剪接事件，可能在蛋白质水平上表现出来。 将建立相关的同工型相互作用和加权共表达网络，以优先考虑特定的剪接 已知癌症途径中的事件。