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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.

摘要成骨细胞是乳腺癌骨转移过程中肿瘤微环境的重要组成部分。它最近已经证明，播散性乳腺癌细胞与成骨细胞利基相互作用存活下来并在骨头上定居。然而，肿瘤细胞和肿瘤细胞之间相互作用的详细机制成骨细胞在骨定植中的生态位大多尚不明确。此外，几乎没有研究表明已阐明成骨细胞在抵抗传统疗法骨转移中的作用 (即化疗和放射治疗)。在我们的初步研究中，我们发现化疗显著提高成骨细胞和间充质干细胞/基质细胞中Jagged1的表达水平 (MSCs)，成骨细胞的前体。Jagged1在成骨细胞中的转基因表达 Col1a1-Jagged1转基因小鼠模型明显增加骨转移的形成。重要的是，我们开发了一种人源化的抗Jagged1(15D11)的单抗，它初步研究显示对骨转移有良好的治疗效果。我们假设 Jagged1在骨髓间充质干细胞和成骨细胞中的表达增加促进骨定植并通过提供生存信号促进化疗耐药和放射耐药。转移的肿瘤细胞。抗Jagged1的中和抗体可阻断骨转移形成和生长，并使他们对传统疗法敏感。Col1a1-Jagged1和一系列健壮小鼠模型将用于骨转移、同种异体移植和异种移植研究，以评估其功能重要性。成骨细胞Jagged1在骨转移形成和治疗耐药中的作用。我们将使用Jagged1 体内中和抗体15D11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，以了解确切的分子化疗导致成骨细胞Jagged1表达升高的途径以及 Jagged1依赖的成骨细胞-肿瘤相互作用促进转移定植和治疗耐药骨瘦如柴。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抗药性。我们还将揭示分子信号/通路负责成骨细胞壁龛在骨定植和治疗耐药中的Jagged1依赖功能。成功 Jagged1中和抗体的临床前测试也将为其在人类身上的应用铺平道路患者在不久的将来。因此，我们相信我们的研究可能会对改善转移性乳腺癌的治疗。

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.