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KLF4-mediated myeloid plasticity in breast cancer recurrence

KLF4介导的乳腺癌复发中的骨髓可塑性

基本信息

批准号：
10401468
负责人：
Walden Ai
金额：
$ 9.74万
依托单位：
BENEDICT COLLEGE
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：
2020-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401468
关键词：
4T1 Ablation Adoptive Transfer Area Basic Science Bone Marrow Bone Marrow Cells Breast Cancer Model Breast Cancer Patient Breast Cancer Prevention Breast cancer metastasis Cell Separation Cells Collaborations Data Development Disseminated Malignant Neoplasm Distant ERBB2 gene Epithelial Fibroblasts Fluorescence GKLF protein Generations Growth Immune Evasion Immune system Immunotherapy Inbred BALB C Mice Incidence Inflammation Label Link Lung Malignant Neoplasms Mammary Neoplasms Mediating Mesenchymal Metastatic Neoplasm to the Lung Modeling Molecular Morbidity - disease rate Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Names Neoplasm Metastasis Nuclear Protein Operative Surgical Procedures Organ Patients Phenotype Primary Neoplasm Proteins Publishing Recurrence Relapse Reporting Role S100A4 gene Signal Transduction Signaling Molecule Site Stromal Cells Stromal Neoplasm Supporting Cell Testing Translational Research Tumor Markers cancer recurrence cell type college design experience immune function knock-down malignant breast neoplasm melanoma monocyte mortality mouse model neoplastic cell new therapeutic target novel novel therapeutic intervention osteopontin overexpression precursor cell prevent therapeutic target transcription factor tumor tumor growth tumor progression

项目摘要

Breast cancer patients have an anomalously high rate of relapse or recurrence from dormancy after surgery or immunotherapy. There is a major lack of understanding of what regulates dormancy, and basic and translational research is badly needed in this area. Thus, characterization of novel cell types and the underlying signaling molecules in tumor recurrence will likely reveal optimal therapeutic targets to prevent/treat breast cancer recurrence from dormancy. At a cellular level, we propose that a specific type of bone marrow-originated cells known as fibrocytes inhibit breast cancer dormancy. This proposal is supported by published data showing that: 1). fibrocytes promote metastatic tumor growth in a mouse model of melanoma. 2). fibrocytes contribute to tumor progression via immune evasion. 3). fibrocytes possess the ability to generate fibroblasts, a major type of stromal cells supporting growth of high grade breast cancer. At a molecular level, we propose that a nuclear protein named Kruppel like factor 4 (KLF4) is critical to the generation of fibrocytes in regulating breast cancer dormancy because: 1). KLF4 deficiency drastically decreased the tumor growth in the metastatic lung in mouse models of breast cancer metastasis. This was accompanied by decreased numbers of fibrocytes. 2). KLF4 expression levels were tightly associated with the efficiencies of fibrocyte generation and expression levels of a protein named fibroblast-specific protein 1 (FSP1). Highly expressed FSP1 has been linked to recurrent mammary tumors. We thus hypothesize that fibrocytes promote breast cancer recurrence from dormancy in a KLF4/FSP1 axis-dependent manner. We designed the following three specific aims to test our hypothesis. In Aim 1, we will isolate KLF4-deficient fibrocyte precursor cells from KLF4-deficient mice. In Aim 2, we will perform a cause-effect study testing whether KLF4 deficiency in fibrocyte precursor cells leads to reduced tumor recurrence in two mouse models of breast cancer. In Aim 3, we will establish a mechanistic link between the KLF4/FSP1 signaling and breast cancer recurrence. We anticipate that our studies will reveal a novel function of KLF4-controlled fibrocytes in breast cancer recurrence from dormancy. Successful completion of the project will be very helpful to determine whether KLF4 or its downstream molecules is a novel therapeutic target to extend tumor dormancy or eradicate dormant tumor cells in breast cancer patients.

乳腺癌患者有异常高的复发率或从休眠后复发