Jagged1-dependent tumor-stromal interactions in bone metastasis

骨转移中Jagged1依赖性肿瘤-基质相互作用

基本信息

批准号：
9218934
负责人：
Yibin Kang
金额：
$ 37.06万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9218934
关键词：
Allografting Antibodies Bioinformatics Biological Assay Blocking Antibodies Bone Development Bone Marrow Bone Pain Breast Cancer Cell Breast Cancer Patient Cell Lineage Cells Clinical Clinical Trials Coculture Techniques Disease Disseminated Malignant Neoplasm Environment Foundations Fracture Future Hematopoietic Human Hypercalcemia Interleukin-6 Lesion Ligands Malignant Bone Neoplasm Mammary Neoplasms Mediating Mediator of activation protein Mesenchymal Metastatic Neoplasm to the Bone Metastatic breast cancer Metastatic to Molecular Molecular Profiling Nerve compression syndrome Osteoblasts Osteoclasts Osteogenesis Pathway interactions Patients Production Radiation Radiation therapy Radioresistance Resistance Role Sampling Series Signal Pathway Signal Transduction Stromal Cells Stromal Neoplasm TNFSF11 gene Testing Therapeutic Effect Time Transgenic Mice Transgenic Organisms Treatment Efficacy Tumor-Derived Up-Regulation Xenograft procedure bisphosphonate bone cancer cell cell type chemotherapy clinical development conventional therapy efficacy testing experimental study humanized monoclonal antibodies improved in vivo malignant breast neoplasm mouse model neoplastic cell neutralizing antibody notch protein osteogenic overexpression pre-clinical research clinical testing response skeletal stem symptom treatment targeted agent targeted treatment therapeutic development therapy resistant traditional therapy tumor tumor microenvironment

项目摘要

Summary Osteoblasts are emerging as a key component of tumor microenvironment in breast cancer bone metastasis. It has been demonstrated recently that disseminated breast cancer cells interact with the osteoblastic niche to survive and colonize the bone. However, the detailed mechanism for the interaction between tumor cells and osteoblastic niche in bone colonization remains mostly uncharacterized. Furthermore, almost no studies have been done to elucidate the functions of osteoblasts in the resistance of bone metastasis to traditional therapies (i.e., chemotherapy and radiation therapy). In our preliminary studies, we discovered that chemotherapy significantly increases Jagged1 expression level in osteoblasts and in mesenchymal stem/stromal cells (MSCs), the precursors of osteoblasts. Transgenic expression of Jagged1 in osteoblasts in our newly created Col1a1-Jagged1 transgenic mouse model significantly increases the formation of bone metastasis. Importantly, we have developed a humanized monoclonal antibody against Jagged1 (15D11), which demonstrated promising therapeutic effects against bone metastasis in preliminary studies. We hypothesize that the increased expression of Jagged1 in MSCs and osteoblasts promote bone colonization of breast cancer and contribute to chemoresistance and radioresistance by providing survival signaling to metastatic tumor cells. Neutralizing antibodies against Jagged1 may block bone metastasis formation and outgrowth, and sensitize them to traditional therapy. Col1a1-Jagged1 and a series of well establish mouse models will be used for bone metastasis allograft and xenograft studies to evaluate the functional importance of osteoblast Jagged1 in bone metastasis formation and treatment resistance. We will use Jagged1 neutralizing antibody 15D11 in vivo to test its synergistic effect with chemotherapy, radiation therapy and osteoclast-targeting therapy. Furthermore, we will perform experiments to understand the exact molecular pathways leading to elevated expression of Jagged1 in osteoblast in response to chemotherapy, as well as Jagged1-dependent osteoblast-tumor interaction in promoting metastatic colonization and treatment resistance in bone. Our proposed studies will confirm the importance of osteoblast Jagged1 in bone metastasis colonization and treatment resistance. We will also reveal molecular signaling/pathways responsible for the Jagged1-dependent function of the osteoblast niche in bone colonization and treatment resistance. Successful pre-clinical testing of Jagged1 neutralizing antibody will also pave the way toward their application in human patients in the near future. Therefore, we believe our study will likely have a significant impact on improving the treatment of metastatic breast cancer.

概括成骨细胞正在成为乳腺癌骨转移中肿瘤微环境的关键组成部分。它最近已经证明，播散性乳腺癌细胞与成骨细胞生态位相互作用，生存并在骨头上定居。然而，肿瘤细胞与肿瘤细胞之间相互作用的详细机制骨定植中的成骨细胞生态位仍然大多不为特征。此外，几乎没有研究表明旨在阐明成骨细胞在抵抗骨转移传统疗法中的功能（即化疗和放射治疗）。在我们的初步研究中，我们发现化疗显着增加成骨细胞和间充质干/基质细胞中的 Jagged1 表达水平 (MSC)，成骨细胞的前体。我们新创建的成骨细胞中 Jagged1 的转基因表达 Col1a1-Jagged1转基因小鼠模型显着增加骨转移的形成。重要的是，我们开发了针对 Jagged1 (15D11) 的人源化单克隆抗体，初步研究显示了针对骨转移的有希望的治疗效果。我们假设 MSCs和成骨细胞中Jagged1表达的增加促进骨定植乳腺癌并通过提供生存信号来促进化学抗性和放射抗性至转移性肿瘤细胞。针对 Jagged1 的中和抗体可能会阻止骨转移形成并生长，并使他们对传统疗法敏感。 Col1a1-Jagged1等一系列成熟鼠标模型将用于骨转移同种异体移植和异种移植研究，以评估功能重要性成骨细胞 Jagged1 在骨转移形成和治疗抵抗中的作用。我们将使用Jagged1 体内中和抗体15D11，测试其与化疗、放疗和化疗的协同作用破骨细胞靶向治疗。此外，我们将进行实验来了解确切的分子导致成骨细胞中 Jagged1 表达升高以响应化疗的途径，以及 Jagged1依赖性成骨细胞-肿瘤相互作用促进转移定植和治疗抵抗在骨头里。我们提出的研究将证实成骨细胞 Jagged1 在骨转移中的重要性定植和治疗耐药性。我们还将揭示负责的分子信号传导/途径成骨细胞生态位在骨定植和治疗抵抗中的 Jagged1 依赖性功能。成功的 Jagged1中和抗体的临床前测试也将为它们在人类中的应用铺平道路近期的患者。因此，我们相信我们的研究可能会对改善治疗转移性乳腺癌。