Role of Bone in Primary and Metastatic Cancer

骨在原发性和转移性癌症中的作用

• 批准号: 10442364
• 负责人: Roberta Faccio
• 金额: $ 35.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10442364
• 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; 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; Population Decreases; Primary Neoplasm; Principal Investigator; Production; Prognosis; Proteins; 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; base; beta catenin; bone; cell killing; cytokine; in vivo; inhibitor; malignant breast neoplasm; mouse model; neoplastic cell; orthotopic breast cancer; overexpression; primary bone cancer; programs; single-cell RNA sequencing; tumor; tumor growth; tumor progression

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，Roberta，博士 抽象的 我们实验室和其他实验室的最新证据表明，原发肿瘤的叛乱会导致变化 在影响居住的造血和间充质群体的骨微环境中。这些 骨微环境的变化发生在肿瘤发展的早期阶段，在任何证据出现之前 转移性播散，并且随着原发肿瘤的进展而变得更加明显，即使在肿瘤中 不会转移到骨头。我们发现未成熟的骨髓细胞数量增加，可以积极地 抑制患有原发性乳腺肿瘤和新诊断阶段小鼠骨髓中的 T 细胞增殖 II-III 乳腺癌患者与对照组的比较。除了免疫群体的变化外，骨骼驻留 通常参与骨形成和骨稳态调节的成骨细胞和骨细胞会做出反应 通过上调各种炎症细胞因子以及 Wnt 信号通路抑制剂来治疗远端肿瘤， 比如Dkk1。这些骨产生的因素中的一些在局部作用以改变基础骨稳态，但是 还可能产生系统性影响，直接或间接影响原发性肿瘤的生长和未来 肿瘤播散到各个部位。 Wnt 信号在骨骼发育、造血和癌症中发挥重要作用。 Dkk1 是 Wnt/β-连环蛋白 抑制剂，已知可抑制骨形成并促进骨吸收。 Dkk1 水平升高通常是 在癌症患者中观察到并与不良预后相关。我们最近报道 Dkk1 上调 由患有原发性乳腺肿瘤和相关癌症的小鼠骨中的成骨细胞和骨细胞产生 成纤维细胞（CAF）存在于原发部位，但水平远低于骨骼中的水平。有趣的是，我们发现 Dkk1 发挥免疫抑制作用，其中和作用通过减少未成熟细胞来减少原发性肿瘤的生长 骨髓细胞群和增强 T 细胞免疫监视。基于这些令人兴奋的发现，我们的中心 假设是骨中的成骨细胞和骨细胞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来转移扩散到多个部位 Dkk1 的生产。目标1。探索骨微环境在肿瘤进展过程中的作用。 该目的的目的是确定骨中 Dkk1 缺失与肿瘤中 Dkk1 缺失的抗肿瘤作用 地点。目标2。确定 Dkk1 调节免疫抑制的机制。此举的目标 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 批准至 10/31/2018） 第 1 页 延续格式页