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:
  • 金额:
    $ 35.31万
  • 依托单位:
  • 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

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
项目主任/首席研究员(最后、第一、中):Faccio, Roberta, PhD

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Effective Treatment of Established Bone Metastases Can Be Achieved by Combinatorial Osteoclast Blockade and Depletion of Granulocytic Subsets.
  • DOI:
    10.1158/2326-6066.cir-21-0232
  • 发表时间:
    2021-12
  • 期刊:
  • 影响因子:
    10.1
  • 作者:
    Capietto AH;Lee S;Clever D;Eul E;Ellis H;Ma CX;Faccio R
  • 通讯作者:
    Faccio R
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Roberta Faccio其他文献

Roberta Faccio的其他文献

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{{ truncateString('Roberta Faccio', 18)}}的其他基金

Role of Osterix+ Osteolineage Cells in Primary and Metastatic Breast Cancer
Osterix 骨细胞在原发性和转移性乳腺癌中的作用
  • 批准号:
    10585653
  • 财政年份:
    2023
  • 资助金额:
    $ 35.31万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 35.31万
  • 项目类别:
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:
    9887365
  • 财政年份:
    2020
  • 资助金额:
    $ 35.31万
  • 项目类别:
Novel Regulators of Inflammatory Arthritis and Bone Erosion
炎症性关节炎和骨侵蚀的新型调节剂
  • 批准号:
    9893817
  • 财政年份:
    2015
  • 资助金额:
    $ 35.31万
  • 项目类别:
REGULATORY PATHWAYS IN OSTEOCLAST FORMATION AND FUNCTION
破骨细胞形成和功能的调节途径
  • 批准号:
    7810845
  • 财政年份:
    2009
  • 资助金额:
    $ 35.31万
  • 项目类别:
Regulatory Pathways in Osteoclasts and Immune Cells during Inflammatory Arthritis
炎症性关节炎期间破骨细胞和免疫细胞的调节途径
  • 批准号:
    8144338
  • 财政年份:
    2006
  • 资助金额:
    $ 35.31万
  • 项目类别:
Regulatory Pathways in Osteoclasts and Immune Cells during Inflammatory Arthritis
炎症性关节炎期间破骨细胞和免疫细胞的调节途径
  • 批准号:
    8719733
  • 财政年份:
    2006
  • 资助金额:
    $ 35.31万
  • 项目类别:
Regulatory Pathways in Osteoclast Formation and Function
破骨细胞形成和功能的调节途径
  • 批准号:
    7672245
  • 财政年份:
    2006
  • 资助金额:
    $ 35.31万
  • 项目类别:
REGULATORY PATHWAYS IN OSTEOCLAST FORMATION AND FUNCTION
破骨细胞形成和功能的调节途径
  • 批准号:
    7289766
  • 财政年份:
    2006
  • 资助金额:
    $ 35.31万
  • 项目类别:
Regulatory Pathways in Osteoclast Formation and Function
破骨细胞形成和功能的调节途径
  • 批准号:
    7483101
  • 财政年份:
    2006
  • 资助金额:
    $ 35.31万
  • 项目类别:

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