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MYC-regulated RNA Binding Protein Networks and Spliced Isoforms Driving Cancer

MYC 调节的 RNA 结合蛋白网络和剪接亚型导致癌症

基本信息

批准号：
10570245
负责人：
OLGA ANCZUKOW-CAMARDA
金额：
$ 58.62万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570245
关键词：
3-Dimensional Address Alternative Splicing Apoptosis Automobile Driving Binding Binding Sites Biological Assay Breast Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast Epithelial Cells Cancer Biology Cancer Cell Growth Cancer Patient Cell Line Cell Proliferation Cell model Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Data Data Set Development Diagnostic Neoplasm Staging Distant Metastasis Dropout Excision Exons FDA approved Failure Gene Expression Regulation Genes Genetic Transcription Genomic approach Goals Growth Human Image In Vitro Individual Invaded Knowledge MYC gene Maintenance Malignant Neoplasms Mammary Neoplasms Methods Molecular Neoplasm Metastasis Oncogenic Oncoproteins Organoids Outcome Pathogenesis Patient-Focused Outcomes Primary Neoplasm Process Protein Isoforms Proteins Proteomics Proto-Oncogene Proteins c-myc RAS genes RNA RNA Splicing RNA-Binding Proteins Regulation Research Resistance Signal Transduction Testing The Cancer Genome Atlas Therapeutic Studies Time Tissues Transcript Tumor Markers Tumor Promotion Tumor Suppressor Proteins cancer cell cell growth chemical standard clinical biomarkers clinical diagnosis clinically relevant functional genomics in vivo inhibitor insight knock-down malignant breast neoplasm mammary migration neoantigens novel novel marker novel strategies novel therapeutic intervention overexpression patient prognosis predictive signature predictive tools public database targeted treatment therapeutic development therapeutic target tool transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumorigenesis tumorigenic

项目摘要

SUMMARY Alternative RNA splicing is a key step in gene expression regulation and contributes to transcriptional diversity by selecting which transcript isoforms are produced in a specific cell at a specific time point. Aberrantly spliced isoforms can impact every one of the hallmarks of cancer, including increased cell proliferation, migration, or resistance to apoptosis. Regulatory splicing factors (SFs) have recently emerged as a new class of oncoproteins and tumor suppressors. In particular, the tumorigenic capacity of the oncogenic transcription factor MYC, which is dysregulated in >50% of human tumors, has been shown to be dependent on the splicing machinery and on at least 3 SFs directly regulated by MYC. However, we currently do not have a comprehensive understanding of which component(s) of the splicing machinery are regulated by MYC, or of the functions of MYC-induced spliced isoforms. The goal of this proposal is to systematically characterize the mechanisms by which MYC-regulated SFs and spliced isoforms drive tumor growth and maintenance. To begin to address this gap in knowledge, in our preliminary studies we used a mammary cell line harboring an inducible form of MYC to greatly expand the number of known SFs regulated by MYC. We uncovered that MYC activation promotes alternative splicing of >4,000 isoforms and expression of 125 SFs. These SFs are also upregulated in MYC-active breast tumors and can be grouped, based on co-expression, into groups or modules. Six SF-modules highly correlate with MYC activity in breast tumors and cell lines, and are enriched in triple negative breast cancer (TNBC). Which of these SFs play a role in MYC-driven transformation, and whether co-expression of multiple MYC-induced SFs has a stronger tumorigenic effect than individual SFs, is not known. Further, co-expression analysis in 33 TCGA tumors of different tissue origin identified an SF-module shared across all MYC-active tumors, suggesting a pan-cancer vulnerability. We hypothesize that MYC regulates a network of SFs which cooperate in tumor pathogenesis and that disrupting this network could provide a novel strategy to slow growth of MYC-driven tumors. Here, we will leverage our expertise in RNA splicing and cancer biology and apply a functional genomics approach to gain novel insights into MYC's oncogenicity. Aim 1 will characterize the function of 6 MYC-induced SF modules and their splicing targets in TNBC tumor growth in vitro and in vivo. Since it is unknown whether MYC regulates a shared set of isoforms in distinct tissues, Aim 2 will identify pan-cancer splicing signatures predictive of MYC activity and clinical outcomes, which may serve as clinical biomarkers, and will deliver putative neo-antigens generated from MYC-induced isoforms. Finally, Aim 3 will implement genomic approaches to determine which MYC-induced isoforms are essential for the growth of MYC-driven cancer cells and patient-derived organoids. This project will reveal fundamental mechanisms by which oncogenic SFs and their target spliced isoforms drive tumorigenesis downstream of MYC. These results could help inform development of therapeutic strategies for tumors driven by MYC, which remains an undruggable target.

总结