Unbiased identification of spliceosome vulnerabilities across cancer

公正地鉴定癌症中剪接体的脆弱性

基本信息

批准号：
10418715
负责人：
Nathan G. Salomonis
金额：
$ 40.67万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418715
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 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 transcription regulatory network transcriptome tumor

项目摘要

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.

项目概要：尽管选择性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，剪接机制可以在癌症中被劫持，以促进转移、免疫逃逸、侵袭和抗- 凋亡行为。虽然剪接因子突变发生在 1-15% 的患者中，具体取决于癌症，新出现的数据表明，常见的失调癌基因（例如 MYC）间接调节 mRNA 导致癌症的加工途径促进不同恶性肿瘤中的选择性剪接亚型。使用最近开发的一系列无监督剪接检测和候选剪接调控预测技术，我们发现剪接在成人和儿童癌症中广泛被破坏，独立于明显的剪接因子突变。这些数据表明了一种潜在的范式转变模型，其中癌症中存在广泛的协调剪接功能障碍，可能是通过剪接因子的不平衡造成的表达、信号传导或基因改变。如果属实，剪接体定向和上游疗法可能是广泛地在癌症中重新利用，重点关注特定的剪接特征和相关的监管途径而不是仅针对特定突变。为了测试这些假设并开发可重复使用的分析为了癌症界的资源，我们提出以下目标。目标 1：通过观察到的致癌事件暗示关键剪接途径的脆弱性多种癌症。我们将利用我们现有的综合多重技术在全球范围内描述选择性剪接的特征涵盖数十种癌症和数千个样本的组学计算工作流程。识别剪接事件使用新颖的无监督或监督分析也将在不同的癌症内部和之间进行比较作为不同来源的正常细胞来定义可重复的肿瘤内在程序与分化相关程序。目标 2：定义并验证儿科 AML 和多种疾病的核心剪接监管网络人类癌症。我们将建立并验证一种新颖的学习模型来定义剪接调节网络儿童 AML 并最终跨越多种成人和儿童癌症。我们将采用当前的最佳实践用于多证据转录调控网络推断剪接并严格测试我们的模型验证数据。一个大型实验剪接因子结合数据集库将用于改进我们的预测。这些分析将鉴定新型剪接调节因子和 RNA 识别元件。目标3：建立精准剪接生物标志物检测和选择性剪接的发现平台目标抑制。我们将开发一个交互式计算界面来识别特定的 RNA 亚型与目标 1 中获得的多种癌症中的不良预后剪接亚型相关。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，我们将能够发现剪接事件与多种基因调控模式相关，可能在蛋白质水平上表现出来。将建立相关的异构体相互作用和加权共表达网络，以优先考虑特定剪接已知癌症途径中的事件。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Resolving single-cell heterogeneity from hundreds of thousands of cells through sequential hybrid clustering and NMF.

通过顺序混合聚类和 NMF 解决数十万个细胞的单细胞异质性。

DOI：
发表时间：
2020-06-01
期刊：
影响因子：
0
作者：
Venkatasubramanian, Meenakshi;Chetal, Kashish;Schnell, Daniel J;Atluri, Gowtham;Salomonis, Nathan
通讯作者：
Salomonis, Nathan

Cannabidiol Treatment Results in a Common Gene Expression Response Across Aggressive Cancer Cells from Various Origins.

大麻二酚治疗会导致不同来源的侵袭性癌细胞产生共同的基因表达反应。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Desprez, Pierre;Murase, Ryuichi;Limbad, Chandani;Woo, Rinette W L;Adrados, Isabel;Weitenthaler, Klemens;Soroceanu, Liliana;Salomonis, Nathan;McAllister, Sean D
通讯作者：
McAllister, Sean D

DeepImmuno: deep learning-empowered prediction and generation of immunogenic peptides for T-cell immunity.

DeepImmuno：基于深度学习的预测和生成用于 T 细胞免疫的免疫原性肽。

DOI：
发表时间：
2021-11-05
期刊：
影响因子：
9.5
作者：
Li, Guangyuan;Iyer, Balaji;Prasath, V B Surya;Ni, Yizhao;Salomonis, Nathan
通讯作者：
Salomonis, Nathan

MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia.

MBNL1 调节 MLL 重排白血病中重要的替代 RNA 剪接模式。

DOI：
发表时间：
2020-05-12
期刊：
影响因子：
16.6
作者：
Itskovich, Svetlana S;Gurunathan, Arun;Clark, Jason;Burwinkel, Matthew;Wunderlich, Mark;Berger, Mikaela R;Kulkarni, Aishwarya;Chetal, Kashish;Venkatasubramanian, Meenakshi;Salomonis, Nathan;Kumar, Ashish R;Lee, Lynn H
通讯作者：
Lee, Lynn H

LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia.

LAMP-5 是一种重要的炎症信号调节剂，也是混合谱系白血病重排急性白血病的新型免疫治疗靶点。

DOI：
发表时间：
2022
期刊：
影响因子：
10.1
作者：
Gracia;Clark, Jason;Burwinkel, Matthew;Greenslade, Brenay;Wunderlich, Mark;Salomonis, Nathan;Leone, Dario;Gatti, Evelina;Pierre, Philippe;Kumar, Ashish R;Lee, Lynn H
通讯作者：
Lee, Lynn H