CHARACTERIZATION OF BREAST CANCER DORMANCY IN BONE

乳腺癌骨休眠的特征

基本信息

批准号：
9346606
负责人：
Rachelle W Johnson
金额：
$ 24.9万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9346606
关键词：
Advisory Committees Automobile Driving Bone Marrow Bone Marrow Cells Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Carcinoma Breast cancer metastasis Cancer cell line Cell Proliferation Cells Clinical Data Development Disease Disease remission Distant Metastasis Down-Regulation Educational workshop Family Fatty acid glycerol esters Foundations Genes Genetic Goals Growth HIF1A gene Home environment Homing Human Hypoxia Hypoxia Inducible Factor IL6ST gene Indolent Institution Interleukin-6 LIF gene Label Laboratories Length MCF7 cell Mammary gland Marrow Mentors Messenger RNA Metastatic Neoplasm to the Bone Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Monitor Morbidity - disease rate Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Osteogenesis Oxygen Patient Care Patients Phenotype Population Primary Neoplasm Process Production Proliferating Protein Overexpression Receptor Signaling Recurrence Research Research Training Role Signal Transduction Signaling Protein Site Survival Rate Testing Therapeutic Time Training Programs United States Universities VHL gene Vascular Endothelial Growth Factors angiogenesis autocrine bone cancer cell cancer recurrence career clinical care clinically significant cytokine glycoprotein 130 in vivo inhibitor/antagonist insight leukemia inhibitory factor receptor malignant breast neoplasm mortality mouse model neoplastic cell novel oncostatin M overexpression parathyroid hormone-related protein prevent receptor therapeutic target transcription factor transcriptome sequencing vasculogenesis

项目摘要

This objective of this proposal is to identify genetic differences between cancer cells that lie dormant in the bone and those that have “re-awakened” from a dormant state, and to discover the mechanisms responsible. These studies will identify potential therapeutic targets for the nearly 3 million breast cancer patients currently in remission. There is sufficient evidence that hypoxia (a lack of oxygen) stimulates parathyroid hormone-related protein (PTHrP) and inhibits leukemia inhibitor factor (LIF) signaling in breast cancer cells, which may control the re-awakening process. Deletion of LIFR or over-expression of PTHrP results in the conversion of weakly metastatic breast cancer cells to invasive and highly metastatic cells, which leads to the hypothesis that hypoxia promotes bone metastasis in part through down-regulation of LIFR signaling, which stimulates cancer cells to exit dormancy through vascular endothelial growth factor (VEGF) production. This will be tested using several current breast cancer models in which LIF and PTHrP signaling is disrupted to determine their effect on mRNAlevel changes in breast cancer cells as they evolve from dormant to proliferative. Weakly bone metastatic human MCF-7 and mouse D2.0R cancer cell lines will be used as models of breast cancer dormancy in bone. These cells will be driven out of dormancy in vivo through LIF signalling inhibition and PTHrP over-expression. GFPlabelled breast cancer cells will be dyed with RFP that is lost as cells divide, and these tags will be used to fractionate dormant vs post-dormant (proliferative) cells in the bone marrow for RNA sequencing. The proposal will also examine the role of hypoxia inducible factor (HIF) and LIF signaling at the primary tumor site on bone metastasis using the MMTV-PyMT spontaneous model of breast cancer and mice lacking HIF1α and HIF2α in the mammary gland. Dr. Johnson’s immediate goal is to establish a dormancy signature for breast cancer cells in the bone that is consistent across multiple models. The proposed project will identify genetic aberrations in dormant vs proliferative cells and lay the foundation for Dr. Johnson to establish an independent laboratory at an academic research institution. Her research training program includes attendance at relevant seminars, workshops, and courses hosted by Stanford University, as well as oversight from co-mentors and a respected career advisory committee she has formed to monitor both career and scientific development.

该提案的目的是确定休眠的癌细胞之间的遗传差异骨骼和那些从休眠状态“重新唤醒”的骨骼，并发现相关机制。这些研究将为目前接受治疗的近 300 万乳腺癌患者确定潜在的治疗靶点。有足够的证据表明缺氧（缺氧）会刺激甲状旁腺激素相关。蛋白 (PTHrP) 并抑制乳腺癌细胞中的白血病抑制因子 (LIF) 信号传导，这可能控制 LIFR 的缺失或 PTHrP 的过度表达导致弱的转变。转移性乳腺癌细胞转变为侵袭性和高度转移性细胞，这导致了缺氧的假设部分通过下调 LIFR 信号来促进骨转移，从而刺激癌细胞退出血管内皮生长因子 (VEGF) 的产生将使用多种方法进行测试。目前的乳腺癌模型中，LIF 和 PTHrP 信号传导被破坏，以确定它们对 mRNA 水平的影响乳腺癌细胞从休眠状态发展为增殖性弱的人类骨转移细胞的变化。 MCF-7和小鼠D2.0R癌细胞系将用作骨中乳腺癌休眠的模型。通过 LIF 信号传导抑制和 PTHrP 过度表达，细胞将摆脱体内休眠状态。乳腺癌细胞将被 RFP 染色，RFP 会随着细胞分裂而丢失，这些标签将用于分离骨髓中的休眠细胞和休眠后（增殖）细胞以进行 RNA 测序。还将检查缺氧诱导因子 (HIF) 和 LIF 信号在骨原发肿瘤部位的作用使用 MMTV-PyMT 乳腺癌自发模型和缺乏 HIF1α 和 HIF2α 的小鼠进行转移乳腺。约翰逊博士的近期目标是在骨骼中建立乳腺癌细胞的休眠特征这在多个模型中是一致的。拟议的项目将识别休眠与休眠中的遗传畸变。增殖细胞，为约翰逊博士在学术界建立独立实验室奠定了基础她的研究培训计划包括参加相关研讨会、讲习班和由斯坦福大学主办的课程，以及共同导师和受人尊敬的职业咨询的监督她成立了委员会来监督职业和科学发展。