A mechanistic dissection of the role of Eya3 in breast cancer metastasis

Eya3在乳腺癌转移中作用的机制剖析

基本信息

批准号：
10410459
负责人：
Hengbo Zhou
金额：
$ 10.33万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2018-09-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410459
关键词：
3-Dimensional Address Animal Model Back Bioinformatics Breast Cancer Cell Breast Cancer cell line Breast cancer metastasis CD8-Positive T-Lymphocytes Cell Line Cells Cessation of life Clinical Communication Development Developmental Process Dissection Embryonic Development Exhibits Family Future Genetic Transcription Goals Growth Immune Immune Evasion Immune response Immune system Immunity Immunocompetent Immunosuppression Immunotherapy Individual Laboratories Laboratory Research Lead Lesion Malignant Neoplasms Mammary Neoplasms Mediating Mentors Modeling Molecular Molecular Biology Mutate N-terminal Natural Immunity Nature Neoplasm Metastasis Pathway interactions Patients Phase Phenotype Phosphoric Monoester Hydrolases Play Protein Family Protein Tyrosine Phosphatase Protein phosphatase Proteins Publications Reporting Research Research Project Grants Role Sampling Scientist Site Structure T cell response Testing Therapeutic Threonine Training Translational Research Tumor Immunity Tumor-infiltrating immune cells Tyrosine Up-Regulation Work Xenograft procedure adaptive immunity base c-myc Genes cellular targeting checkpoint therapy cofactor design druggable target exhaustion experience experimental study immune checkpoint improved in vivo insight interest intravital imaging knock-down malignant breast neoplasm member mouse model neoplastic cell novel patient subsets premalignant prevent programmed cell death ligand 1 reconstruction response side effect skills therapeutic target transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

Project Summary It is well-accepted that deregulated immunity is a major contributor to tumor growth and progression. Tumor cells have been demonstrated to transform the microenvironment into an immune-suppressive niche to facilitate their growth. Therefore, dissecting the mechanisms by which tumor cells regulate the immune compartment is instrumental to providing insights for the improvement and development of immune therapies. In the thesis work of this project, I am investigating the roles of Eya3 in immunosuppression and tumor progression. Eya3 is a member of a family of multifunctional Eya proteins, which contain transactivating potential, and completely separable Tyrosine (Tyr) and Threonine (Thr) phosphatase activities. Interestingly, their expression is not only associated with normal development, but is often altered in tumors. Eya3 is most expressed in the highly aggressive form of breast cancer, triple negative breast cancer (TNBC). The role of the Thr phosphatase activity of Eya in cancer has not been studied, yet its transactivating potential and Tyr phosphatase activity have both been implicated in breast cancer metastasis. My studies on the Thr phosphatase activity of Eya3 have resulted in novel findings. First, I have shown that in contrast to the previous notion that Eya3 possesses intrinsic Thr phosphatase activity, Eya3 interacts with PP2A to exhibit Thr phosphatase activity. This associated activity enhances c-Myc stability, resulting in upregulation of the immune checkpoint protein PD-L1, dampening anti-tumor T-cell responses. This work is the first demonstration of a role for TNBC expressed Eya3 in regulating adaptive immunity and tumor progression. In this F99/K00 proposal, I describe a research strategy to complete my dissertation studies, and outline the direction I would like to take in my postdoctoral years. In Aim 1a, I describe my findings to date, which are described above and have resulted in one co-first author publication in Nature Communications (in press) as well as a second author publication in revision at J Clin Invest. Aim 1b outlines my research plan for completion of my dissertation studies, where I examine which activity of Eya3 is most required for its tumor promotional effects (with the idea that this will aid in therapeutic targeting of the correct activity), and I will further identify which targets (using both a targeted and unbiased approach) of Eya3 mediate phenotypes associated with various activities. In Aim 2, I focus on what I would like to work on in my postdoctoral years (K00). It has been reported that tumor cells can disseminate from a pre-malignant lesion, and these disseminated tumor cells (DTC) are able to remain dormant, and eventually re-grow into lethal metastases. Thus, gaining a better understanding of the mechanisms by which tumor cells maintain and exit dormancy will provide insights for developing therapeutic strategies to keep tumor cells in dormancy or to specifically eliminate dormant tumor cells. Aim 2 focuses on exploring how the dynamic tumor microenvironment impinges on dormancy of DTCs, in an attempt to identify druggable molecules, unique to tumor-stroma crosstalk, that are necessary for the break of dormancy.

项目摘要众所周知，放松管制的免疫力是肿瘤生长和进展的主要因素。瘤已经证明细胞将微环境转化为免疫抑制的利基市场促进他们的成长。因此，解剖肿瘤细胞调节免疫的机制隔室有助于为改善和开发免疫疗法提供见解。在该项目的论文工作中，我正在研究EYA3在免疫抑制和肿瘤中的作用进展。 EYA3是多功能EYA蛋白家族的成员，其中包含反式激活潜力，完全可分离的酪氨酸（Tyr）和苏氨酸（THR）磷酸酶活性。有趣的是，它们的表达不仅与正常发育有关，而且通常会改变肿瘤。 eya3是最大的以高度侵略性的乳腺癌形式表达，三重阴性乳腺癌（TNBC）。角色尚未研究EYA在癌症中的磷酸酶活性磷酸酶的活性都与乳腺癌转移有关。我对THR的研究 EYA3的磷酸酶活性已导致新发现。首先，我证明了这与以前的相反 Eya3具有内在的THR磷酸酶活性，EYA3与PP2A相互作用以表现出THR 磷酸酶活性。这种相关的活动增强了C-MYC稳定性，导致免疫的上调检查点蛋白PD-L1，抑制抗肿瘤T细胞反应。这项工作是角色的首次演示对于TNBC，在调节适应性免疫和肿瘤进展方面表达了EYA3。在此F99/K00建议中，我描述了一项研究策略，以完成论文研究，并概述我想迎来博士后时。在AIM 1A中，我描述了迄今为止的发现，上面描述并导致了自然传播（印刷中）的共同首先作者出版物以及J Clin Invest修订版的第二个作者出版物。目标1B概述了我的研究计划在我的论文研究中，我检查了eya3的肿瘤促进最需要的哪种活动效果（以下想法，这将有助于治疗靶向正确的活动），我将进一步确定 eya3介导与各种活动。在AIM 2中，我专注于在博士后年（K00）中想从事的工作。它一直报道肿瘤细胞可以从恶性病变中传播，这些弥散性肿瘤细胞（DTC）能够保持休眠状态，并最终重长为致命转移。因此，获得更好的理解肿瘤细胞维持和退出休眠的机制将为发展提供见解使肿瘤细胞处于休眠状态或专门消除休眠肿瘤细胞的治疗策略。目标2 专注于探索动态肿瘤微环境如何影响DTC的休眠鉴定可药物分子，这是肿瘤性串扰所特有的，这是休眠破裂所必需的。