Role of Bone in Primary and Metastatic Cancer

骨在原发性和转移性癌症中的作用

基本信息

批准号：
10671085
负责人：
Roberta Faccio
金额：
$ 35.31万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671085
关键词：
4T1 Affect Biological Assay Bone Development Bone Marrow Bone Resorption Bone Tissue Bone neoplasms Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Carcinoma Cancer Patient Cell Differentiation process Cell Proliferation Cells Clinical Cluster Analysis Communication Complement Data Development Disseminated Malignant Neoplasm Distal Doctor of Philosophy Environment Fibroblasts Future Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Hematopoiesis Hematopoietic Homeostasis Immune Immunologic Surveillance Immunosuppression In Vitro Inflammatory Interleukin-6 Lead Lewis Lung Carcinoma Macrophage Colony-Stimulating Factor Malignant Neoplasms Mammary Neoplasms Mesenchymal Mouse Mammary Tumor Virus Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Natural Killer Cells Neoplasm Metastasis Newly Diagnosed Organ Osteoblasts Osteocytes Osteogenesis Play Population Primary Neoplasm Principal Investigator Production Prognosis Proteins Publishing Regulation Reporting Role Site Source Spleen Suppressor-Effector T-Lymphocytes T-Cell Activation T-Cell Proliferation T-Lymphocyte TNFSF11 gene Tissue Microarray Tumor stage WNT Signaling Pathway Work antitumor effect beta catenin bone cell killing cytokine immunoregulation in vivo inhibitor malignant breast neoplasm melanoma mouse model neoplastic cell orthotopic breast cancer overexpression polyoma middle tumor antigen primary bone cancer programs single-cell RNA sequencing skeletal tumor tumor growth tumor progression

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Faccio, Roberta, PhD ABSTRACT Recent evidence from our lab and others indicates that the insurgence of a primary tumor leads to changes in the bone microenvironment that affect the residing hematopoietic and mesenchymal populations. These changes in the bone microenvironment occur during the early stages of tumor development, prior to any evidence of metastatic dissemination, and become more pronounced while the primary tumor progresses, even in tumors that do not metastasize to the bone. We find increased numbers of immature myeloid cells that can actively suppress T cell proliferation in bone marrow of mice bearing primary breast tumors and in newly diagnosed stage II-III breast cancer patients compared with controls. In addition to changes in immune populations, bone residing osteoblasts and osteocytes, normally involved in bone formation and regulation of bone homeostasis, respond to distal tumors by upregulating various inflammatory cytokines as well as inhibitors of the Wnt signaling pathway, such as Dkk1. Several of these bone-produced factors act locally to change the basal bone homeostasis, but can also have systemic effects that can impact, either directly or indirectly, primary tumor growth and future tumor dissemination to various sites. Wnt signaling plays important roles in bone development, hematopoiesis and cancer. Dkk1 is a Wnt/β-catenin inhibitor, known to suppress bone formation and promote bone resorption. Increased levels of Dkk1 are often observed in cancer patients and correlate with poor prognosis. We recently reported that Dkk1 is upregulatated by osteoblasts and osteocytes in the bone of mice with primary breast tumors and in cancer associated fibroblasts (CAFs) in the primary site, but at a level much lower than in the bone. Intriguingly, we found that Dkk1 exerts immune suppressive effects and its neutralization decreases primary tumor growth by reducing immature myeloid populations and enhancing T cell immune surveillance. Based on these exciting findings, our central hypothesis is that bone residing osteoblasts and osteocytes modulate primary breast cancer growth and metastatic dissemination to multiple sites by creating a systemic immune suppressive environment via production of Dkk1. Aim1. Exploring the role of the bone microenvironment during tumor progression. The goal of this aim is to determine the anti-tumor effects of Dkk1 deletion in bone versus its deletion at tumor site. Aim2. Determine the mechanism by which Dkk1 modulates immune suppression. The goal of this aim is to determine the cellular mechanism by which Dkk1 induces immune suppression. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page 1 Continuation Format Page

项目总监/首席研究员（最后，第一，中间）：FACCIO，罗伯塔，博士抽象的我们实验室和其他实验室的最新证据表明，原发性肿瘤的损伤导致变化在骨微环境中影响居住的造血和间充质种群。这些骨微环境的变化发生在肿瘤发育的早期阶段，在任何证据之前转移性传播，并且在原发性肿瘤进行时，即使在肿瘤中也变得更加明显不会转移到骨头。我们发现可以主动的未成熟髓样细胞数量增加抑制带有原发性乳腺肿瘤的小鼠的骨髓中的T细胞增殖，并在新诊断的阶段 II-III乳腺癌患者与对照组相比。除了免疫吞吐量的变化外，骨头还居住骨细胞和骨细胞通常参与骨形成和骨体内平衡的调节，反应通过上调各种炎症细胞因子以及Wnt信号通路的抑制剂来远端肿瘤，例如DKK1。这些骨产生的因素中有几个在本地起作用，以改变基本的骨体内稳态，但还可能会产生直接或间接影响原发性肿瘤生长和未来的全身效应肿瘤传播到各个部位。 Wnt信号传导在骨骼发育，造血和癌症中起着重要作用。 DKK1是Wnt/β-catenin 已知可以抑制骨形成并促进骨骼分辨率的抑制剂。 DKK1的水平升高通常是在癌症患者中观察到，与预后不良相关。我们最近报告说DKK1已上调通过原发性乳腺肿瘤的小鼠骨骼中的成骨细胞和骨细胞和癌症相关的骨细胞主要部位的成纤维细胞（CAF），但水平远低于骨骼。有趣的是，我们发现DKK1 发挥免疫抑制作用及其神经化作用，通过减少未成熟来下降原发性肿瘤的生长髓样群体并增强T细胞免疫监测。根据这些令人兴奋的发现，我们的中央假设是居住成骨细胞和骨细胞的骨调节原发性乳腺癌的生长和通过创建系统性免疫抑制环境，通过转移到多个站点 DKK1的生产。 AIM1。探索骨微环境在肿瘤进展过程中的作用。此目的的目的是确定骨骼中DKK1缺失的抗肿瘤效应与肿瘤的缺失地点。 AIM2。确定DKK1调节免疫抑制的机制。目标的目标目的是确定DKK1诱导免疫抑制的细胞机制。 OMB编号0925-0001/0002（修订版03/16批准通过10/31/2018）第1页连续格式页面