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：
10064995
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/10064995
关键词：
3-Dimensional Allografting Antibodies Bioinformatics Biological Assay Blocking Antibodies Bone Development Bone Marrow Bone Pain Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cell Lineage Cells Chemoresistance Chemotherapy and/or radiation Clinical Clinical Trials Coculture Techniques Disease Disseminated Malignant Neoplasm Environment Expression Profiling 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 Nerve compression syndrome Osteoblasts Osteoclasts Osteogenesis Pathway interactions Patients Preclinical Testing Production Radiation Radiation therapy 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 colonization resistance 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 radiation resistance 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。它最近已经证明了传播乳腺癌细胞与成骨细胞的相互作用生存并定居骨头。但是，肿瘤细胞与骨定植中的成骨细胞生态市场主要是未表征的。此外，几乎没有研究已完成以阐明成骨细胞在骨转移对传统疗法的抗性中的功能（即化学疗法和放射疗法）。在我们的初步研究中，我们发现化学疗法显着提高成骨细胞和间充质茎/基质细胞中的锯齿状1表达水平（MSC），成骨细胞的前体。在我们新创建的成骨细胞中Jagged1的转基因表达 COL1A1-果酱1转基因小鼠模型显着增加了骨转移的形成。重要的是，我们已经开发了一种针对Jagged1（15d11）的人性化的单克隆抗体，该抗体在初步研究中，证明了对骨转移的有希望的治疗作用。我们假设 MSC和成骨细胞中锯齿状1的表达增加促进了骨定殖的乳腺癌并通过提供生存信号来促进化学耐药性和放射线转移性肿瘤细胞。中和针对JAGGED1的抗体可能会阻塞骨转移的形成和生长，使它们对传统疗法敏感。 col1a1-jagged1和一系列良好的鼠标模型将用于骨转移同种异体移植和异种移植研究，以评估功能重要性骨转移和治疗耐药性中的成骨细胞锯齿状1。我们将使用锯齿中和抗体15d11在体内测试其通过化学疗法，放射治疗和破骨细胞靶向疗法。此外，我们将进行实验以了解精确的分子响应化学疗法以及在促进转移性定植和治疗耐药性方面，JAGGED1依赖性成骨细胞相互作用在骨头。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殖和治疗耐药性。我们还将揭示负责的分子信号传导/途径成骨细胞生丁基在骨定殖和治疗耐药性中的锯齿状1依赖性功能。成功的 JAGGED1中和抗体的临床前测试也将为其在人类中的应用铺平道路病人在不久的将来。因此，我们认为我们的研究可能会对改善治疗转移性乳腺癌。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis.

DOI：
10.1038/s41556-021-00641-w
发表时间：
2021-03
期刊：
Nature cell biology
影响因子：
21.3
作者：
Esposito M;Fang C;Cook KC;Park N;Wei Y;Spadazzi C;Bracha D;Gunaratna RT;Laevsky G;DeCoste CJ;Slabodkin H;Brangwynne CP;Cristea IM;Kang Y
通讯作者：
Kang Y

The Biology of Bone Metastasis.