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

基本信息

批准号：
10585653
负责人：
Roberta Faccio
金额：
$ 40.99万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-20 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585653
关键词：
4T1 Adoptive Transfer Adult Affect Antigen Presentation Biological Assay Bone Marrow Bone Marrow Transplantation Breast Carcinoma Cell Separation Cells ChIP-seq Circulation Complement Deposition Development Disease Distant Ectopic Expression Embryo Environment Extracellular Matrix Fibroblasts Generations Genes Genetic Growth Growth Factor Heterogeneity Immune Infiltration Injections Interruption Investigation Lung Malignant Neoplasms Mammary Neoplasms Mesenchymal Metastatic breast cancer Mus Neoplasm Metastasis Normal Cell Osteoblasts Patients Population Production Prognosis Reporter Genes Role Site Skeleton Soil Source Specificity Stromal Cells Surface Transplantation Tumor Markers bone breast cancer progression cancer cell cancer therapy cytokine design fighting immunoregulation malignant breast neoplasm mammary mature animal mesenchymal stromal cell mouse model neoplastic cell novel novel marker novel therapeutic intervention osteogenic polyoma middle tumor antigen postnatal premalignant progenitor promoter recruit response single-cell RNA sequencing skeletal skeletal stem cell transcription factor tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

ABSTRACT In order to survive, grow and metastasize, tumors need the support of a favorable host environment. Local changes in normal cells in close proximity to a developing tumor can create a favorable tumor micro-environment (TME) that is necessary for tumor growth. Mesenchymal populations, including cancer-associated fibroblasts (CAFs), secrete pro- tumorigenic and immune suppressive factors, and produce extracellular matrix to create a stiffer, tumor-conducive soil. Several CAF subsets with specific functions have been identified, however, whether distinct CAF subsets derive from the same progenitor that acquire functional specificity during tumor progression or from different progenitors committed to give rise to a specific CAF population, is under investigation. We recently made the unexpected observation that cells expressing bone osteolineage marker Osterix (Osx) are present in the TME of tumors outside the bone and support tumor growth. In adult animals, Osx is expressed by committed osteoblasts (OB) and drives their differentiation. Surprisingly, we detected Osx in stromal cells, isolated from various breast cancer tumors, expressing CAF and OB makers, and in the tumor-associated stroma of patients with breast carcinomas. Co-injection of Osx+ cells with tumor cells enhance tumor growth. Importantly, Osx expression correlates with poor prognosis in breast cancer. Based on these rather unexpected findings, we hypothesize that bone-derived osteolineage Osx+ cells represent a novel subset of tumor infiltrating stromal populations contributing to tumor progression and CAF diversity. Aim 1 will determine the functional relevance of Osx+ cells in the TME and pre-metastatic sites; Aim 2 will determine the origin of Osx+ cells in the TME and pre-metastatic sites. This information will broaden the concept of cellular heterogeneity within the TME and offer a new platform for targeting the stroma with the purpose of inhibiting tumor growth.

抽象的为了生存，生长和转移，肿瘤需要有利的宿主环境的支持。当地的正常细胞与发育中的肿瘤紧邻的变化会产生有利的肿瘤微环境（TME）是肿瘤生长所必需的。间充质种群，包括癌症相关的成纤维细胞（CAFS），分泌肿瘤和免疫抑制因素，并产生细胞外基质以创建一个僵硬，肿瘤有用的土壤。但是，已经确定了几个具有特定功能的CAF子集独特的CAF子集源自在肿瘤进展过程中获得功能特异性的同一祖细胞或来自承诺引起特定CAF人群的不同祖细胞正在研究。我们最近对表达骨骼骨丁质标记的细胞Osterix（OSX）进行了意外观察存在于骨外肿瘤的TME中并支持肿瘤生长。在成年动物中，OSX由犯有成骨细胞（OB）并驱动其分化。令人惊讶的是，我们在基质细胞中检测到OSX，从各种乳腺癌肿瘤中分离出来，表达CAF和OB制造商，以及在肿瘤相关的基质中患有乳腺癌的患者。 OSX+细胞与肿瘤细胞共同注射可增强肿瘤的生长。重要的是，OSX表达与乳腺癌的预后不良相关。基于这些相当出乎意料的调查结果，我们假设骨衍生的骨丁质OSX+细胞代表了肿瘤浸润的新型子集基质种群有助于肿瘤进展和CAF多样性。 AIM 1将决定功能 OSX+细胞在TME和中转移部位的相关性； AIM 2将确定OSX+细胞在 TME和前移位部位。此信息将扩大TME中细胞异质性的概念并提供一个针对基质的新平台，目的是抑制肿瘤生长。