UBR5's mechanisms of action in tumorigenesis and immunoregulation

UBR5在肿瘤发生和免疫调节中的作用机制

基本信息

批准号：
10659844
负责人：
XIAOJING MA
金额：
$ 65.52万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659844
关键词：
BRCA1 Mutation Binding Biochemical Biology C-terminal CD8-Positive T-Lymphocytes CTLA4 gene Cancer Patient Cartoons Cells Characteristics Chimera organism Chromatin Cisplatin Clinical Combination immunotherapy Complex Cytotoxic T-Lymphocytes DNA Sequence Alteration Data Development Gene Amplification Gene Expression Profile Genes Genetic Transcription Genetically Engineered Mouse Growth Human IRF1 gene Immune checkpoint inhibitor Immunosuppression In Vitro Interferons Intervention Lesion Macrophage Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Mammary Neoplasms Mediating Modeling Molecular Mutation Neoplasm Metastasis Nodule Oncogenes Outcome Study PRKR gene Pathway interactions Play Poly A Polyadenylation Polyubiquitination Property Proteins Proto-Oncogenes RNA Polymerase II Regulation Role STAT1 gene Science Signal Induction Signal Pathway Signal Transduction Site Structure-Activity Relationship Testing Therapeutic Therapeutic Intervention Time Transcriptional Regulation Tumor Escape Tumor Suppressor Proteins Tumor-Derived Validation Work cancer cell chemokine chemotherapy docetaxel experimental study genome-wide immune checkpoint immunoregulation in vivo innovation malignant breast neoplasm mammary epithelium multicatalytic endopeptidase complex neoplastic cell novel novel therapeutics overexpression pharmacologic posttranscriptional programmed cell death ligand 1 programmed cell death protein 1 programs protein degradation prototype recruit therapy resistant transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumorigenesis tumorigenic ubiquitin-protein ligase

项目摘要

Clinical analyses show that UBR5 gene amplifications and overexpression occur in 10-40% cases of many major types of aggressive human cancers. Furthermore, breast, ovarian and prostate cancer patients carrying genetic alterations in UBR5 have significantly reduced survivals compared to those without the lesions. Our experimental work in vitro and in vivo has first demonstrated that UBR5, functioning like an “oncogene”, plays a profound role in promoting breast and ovarian cancer growth and metastasis. We have also shown that tumor-derived UBR5 drives malignant triple negative mammary tumor growth through both cell-intrinsic and extrinsic mechanisms, whereas it facilitates metastasis primarily in a tumor cell-autonomous manner. Thus, further elucidating UBR5’s fundamental biology and identifying critical signaling nodules controlled by UBR5 in its potent tumorigenic and immunoregulatory activities will not only advance the science but also help the development of novel therapies for highly malignant breast cancer that evades the endogenous cellular control mechanisms and resist current interventional strategies. We hypothesize that UBR5 promotes aggressive BC/TNBC via distinct mechanisms that include controlling the CDC73 protein turnover in an E3 ubiquitin ligase-dependent manner and enhancing Interferon-g-induced transcription of the PDL1 gene and others in an E3 ligase- independent manner. We propose to broaden and expand the exploration of the cellular and molecular mechanisms of these modulations in two major specific aims. (1) To characterize the biochemical basis of CDC73 protein regulation by UBR5 acting as an E3 ubiquitin ligase; and investigate the role of the chemokine CXCL16 in mediating CDC73’s immunostimulatory activities via recruitment of cytotoxic T lymphocytes to the tumor site. (2) To investigate the cellular and molecular mechanism whereby UBR5 broadly enhances the IFN--activated signaling pathway independently of the E3 ligase activity and explore the therapeutic potential of pharmacological UBR5 inhibition. The outcome of these studies will pave the way for developing innovative therapeutic strategies for highly aggressive and therapy-resistant breast cancer by targeting UBR5 and/or its crucial signaling pathways.

临床分析显示UBR5基因扩增和过度表达发生在10-40%的病例中许多主要类型的侵袭性人类癌症。携带 UBR5 基因改变的癌症患者的生存率显着降低与没有病变的实验相比，我们的体外和体内实验工作具有第一。证明 UBR5 像“癌基因”一样发挥作用，在促进我们还发现肿瘤来源的 UBR5 与乳腺癌和卵巢癌的生长和转移有关。通过细胞内在和外在驱动恶性三阴性乳腺肿瘤生长机制，而它主要以肿瘤细胞自主的方式促进转移。因此，进一步阐明 UBR5 的基本生物学并识别关键信号传导结节由 UBR5 控制的有效致瘤和免疫调节活性不仅会促进科学还有助于开发高度恶性乳腺癌的新疗法逃避内源性细胞控制机制并抵抗当前的介入策略。我们发现 UBR5 通过不同的机制促进攻击性 BC/TNBC，其中包括以 E3 泛素连接酶依赖性方式控制 CDC73 蛋白周转，并且在 E3 连接酶中增强干扰素 g 诱导的 PDL1 基因和其他基因的转录我们建议以独立的方式拓宽和扩展对蜂窝和技术的探索。这些调节的分子机制有两个主要的具体目标。 (1) 表征 UBR5 作为调节因子对 CDC73 蛋白调节的生化基础 E3泛素连接酶；并研究趋化因子CXCL16在介导CDC73中的作用通过将细胞毒性 T 淋巴细胞募集到肿瘤部位来发挥免疫刺激活性。 (2) 研究UBR5广泛增强的细胞和分子机制独立于 E3 连接酶活性的 IFN-γ 激活信号通路，并探索药理学UBR5抑制的治疗潜力。这些研究的结果将为开发创新治疗策略铺平道路通过靶向 UBR5 和/或其关键的乳腺癌治疗高度侵袭性和治疗耐药性乳腺癌信号通路。