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
• 负责人: Roberta Faccio
• 金额: $ 40.99万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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

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.

摘要