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Tissue-Regulated Lineage-Specific Splicing in Glioblastoma Pathogenesis

胶质母细胞瘤发病机制中组织调节的谱系特异性剪接

基本信息

批准号：
10247590
负责人：
Markus Bredel
金额：
$ 34.9万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247590
关键词：
Address Adult Affect Alternative Splicing Amino Acids Annexins Attenuated Binding Brain Brain Neoplasms Cell Lineage Cells Clinical Complex Data Development Disease Endocytosis Epidermal Growth Factor Receptor Exclusion Exocytosis Exons Foundations Future Genetic Glioblastoma Glioma Knowledge Length Malignant - descriptor Malignant Glioma Mediating Membrane Mission Mitotic Modeling N-terminal Neoplasms Neurons Nuclear Pore Complex Oncogenic PDGFRA gene Pathogenesis Pathway interactions Patients Pattern Polypyrimidine Tract-Binding Protein Prevalence Process Protein Isoforms Protein Tyrosine Kinase Public Health RNA Binding RNA Splicing Receptor Protein-Tyrosine Kinases Recycling Regulation Research Role Signal Transduction Sorting - Cell Movement Testing Tissues Tumor Suppressor Genes Tumor Suppressor Proteins Tumorigenicity United States National Institutes of Health Variant Work Xenograft procedure base cell growth epidermal growth factor receptor VIII exon skipping extracellular extracellular vesicles gain of function in vivo knock-down mRNA Precursor neoplastic cell novel novel therapeutics precursor cell prevent progenitor prototype receptor receptor recycling relating to nervous system response stem cells targeted treatment therapeutic target trafficking trait tumor tumorigenesis tumorigenic vesicle transport virtual

项目摘要

PROJECT SUMMARY Lineage-specific alternative splicing, where splicing occurs in a tissue-regulated manner involving evolutionary conserved alternative exons, has a determinative role in brain development. The role of tissue-specific alternative exons in malignant transformation and tumor development is undefined. The impact of lineage- specific splicing on glioblastoma (GBM) pathogenesis remains unclear but is conceptually attractive given the prevalence of this process in determining the fate of ancestral cells of potential GBM origin. We found that brain-enriched splice factor PTBP1 mediates lineage-specific alternative splicing of the ANXA7 tumor suppressor gene. PTBP1 is expressed in neural and glial precursor cells (NPCs/GPCs) and binds ANXA7 pre-mRNA to skip exon 6; this produces spliced ANXA7 isoform 2 (I2). During lineage specification, PTBP1 is downregulated and this allows the expression of unspliced ANXA7 I1 (I1), which includes exon 6. We determined that the patterned expression of the I2 splice variant in the brain is restricted to lineages that represent potential GBM cells of origin but that I1 is virtually absent in these cells. Our preliminary data illustrate that lineage-specific splicing can augment genetic mechanisms to deregulate oncogenic pathways. Specifically, we showed ANXA7 I1, but not I2, targets oncogenic receptor tyrosine kinases (RTKs) such as EGFR, MET and PDGFRA for endosomal degradation. In the adult brain, PTBP1 is nearly absent; in GBM, PTBP1 aberrantly persists and RTK levels are elevated. However, we demonstrate that upon PTBP1 knockdown and/or, ANXA7 I1 re-expression, RTK signaling is reduced, and GBM tumorigenicity is diminished. Therefore, we hypothesize that GBMs benefit from persistent PTBP1 expression as this suppresses ANXA7 I1, prevents RTK endosomal degradation, and sustains RTK signaling in GBM. Our Specific Aims are: 1. Define the Mechanism by which ANXA7 I1 Regulates Endosomal and Cellular Trafficking of EGFR. Herein, we will determine the detailed mechanism by which ANXA7 I1 interacts with and regulates endosomal and extracellular vesicle transport of EGFR as a prototype RTK. 2. Demonstrate ANXA7 I1 is a Signaling Modulator for Multiple RTKs and RTK-Targeted Therapies by Perpetuating Endosomal Degradation. Herein, we will demonstrate that ANXA7 I1 is competent to attenuate signaling through multiple pro-tumorigenic RTKs, modulate TKI response, and thus has a broad impact on GBM in vivo. These mechanistic and focused aims are needed to better define the role of lineage-specific splicing processes in tumorigenesis, which remains understudied. Our results will determine that ANXA7 I1 is sufficient to simultaneously inhibit signaling by multiple RTKs and thus holds potential to reveal a new therapeutic direction. This work will define the role of aberrant lineage-specific alternative splicing in GBM pathogenesis, offer a broader understanding of this process in malignant transformation, and provide a potential foundation for future studies to therapeutically target developmentally regulated splicing factors.

项目总结