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.

该提议的这个目标是确定处于休眠的癌细胞之间的遗传差异骨头和那些从休眠状态“重新唤醒”的骨骼，并发现造成的机制。这些研究将确定目前近300万乳腺癌患者的潜在治疗靶标缓解。有足够的证据表明缺氧（缺氧）刺激甲状旁腺与马酮有关蛋白质（PTHRP）并抑制乳腺癌细胞中的白血病抑制剂因子（LIF）信号传导，这可能控制重新唤醒过程。 LIFR的删除或PTHRP的过表达导致弱转化转移性乳腺癌细胞对侵入性和高度转移性细胞，这导致假设缺氧通过下调LIFR信号传导，促进骨转移，这刺激了癌细胞至通过血管内皮生长因子（VEGF）产生的出口休眠。这将使用几个当前的乳腺癌模型中断了LIF和PTHRP信号传导以确定其对MRNALEVEL的影响乳腺癌细胞从休眠变为增殖时的变化。弱骨转移性人 MCF-7和小鼠D2.0R癌细胞系将用作骨骼中乳腺癌休眠的模型。这些通过LIF信号传导抑制和PTHRP过表达，细胞将被驱逐出体内休眠。 gfplabell 乳腺癌细胞将用RFP染色，而RFP随着细胞分裂而丢失，这些标签将用于骨髓中的分级休眠与休眠后（增殖）细胞进行RNA测序。提案还将检查缺氧诱导因子（HIF）和LIF信号在骨骼上原发性肿瘤部位的作用使用缺乏HIF1α和HIF2α的小鼠的MMTV-PYMT自发模型的转移乳腺。约翰逊博士的直接目标是建立骨骼乳腺癌细胞的休眠签名在多个模型之间是一致的。拟议的项目将确定休眠与扩散细胞并为约翰逊博士建立独立实验室的基础研究机构。她的研究培训计划包括参加相关的半手，研讨会和由斯坦福大学主持的课程，以及副主持人的监督和受人尊敬的职业咨询她成立了委员会，以监视职业和科学发展。