Bone marrow niche regulation of disseminated tumor cell dormancy, reactivation, and metastasis.

播散性肿瘤细胞休眠、重新激活和转移的骨髓生态位调节。

基本信息

批准号：
10569646
负责人：
Grace Gilmore Bushnell
金额：
$ 11.17万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10569646
关键词：
Antibodies Award Biocompatible Materials Bioinformatics Biological Assay Biopsy Biopsy Specimen Blood Vessels Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Bone marrow biopsy Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cancer Biology Cause of Death Cell Communication Cell Line Cells Characteristics Classification Clinical Clinical Oncology Coculture Techniques Consult Cues Cytometry Data Development Diagnosis Elements Estrogen receptor positive Evaluation Exhibits Gel Hematopoietic Hormone Responsive Hormones Hydrogels Image Immune Immunocompetent In Vitro Inflammation Learning Life Maintenance Mechanics Mentors Microscopy Modeling Molecular Biology Mus Nature Neoplasm Metastasis Normal tissue morphology Optics Paracrine Communication Pathology Patients Phase Phenotype Play Population Prevention Prognostic Factor Proliferating Recurrence Recurrent disease Regulation Regulatory Pathway Relapse Research Risk Role Sampling Series Source Stressful Event Testing Three-Dimensional Imaging Tissues Training Work biomarker identification bone cancer cell cancer stem cell experience high dimensionality high risk human disease in vivo malignant breast neoplasm mechanotransduction mouse model neoplastic cell novel predictive modeling prevent programs protein biomarkers recruit single-cell RNA sequencing stem stem cell niche therapeutic development therapeutic target therapy development tissue stem cells tumor

项目摘要

PROJECT SUMMARY / ABSTRACT Metastatic relapse may occur in patients with ER+ breast cancer decades after original diagnosis. Most breast cancer related deaths are caused by metastasis and thus identifying at-risk patients and developing therapies to prevent reactivation are a crucial challenge. These efforts have been impeded by a lack of understanding of cancer cell dormancy in the bone marrow, believed to be the cellular source of metastatic relapse. It is not well understood how tumor cells interact with the bone marrow microenvironment and how these interactions regulate tumor cell dormancy and escape. My proposed research seeks to develop a mouse model of dormancy and investigate the spatial organization of the bone marrow niche in patient samples in the mentored K99 phase and develop a biomaterial model of dormancy in the independent R00 phase. I hypothesize (i) cancer stem cells are a subset of disseminated tumor cells responsible for metastatic relapse and (ii) the bone marrow niche, including the healthy stem cell niche, facilitates dormancy and reactivation of these cells. In Aim 1, I will develop a novel mouse model of hormone responsive breast cancer dormancy in bone marrow and evaluate the presence, phenotype, and microenvironmental regulation of disseminated tumor cells using optical tissue clearing/3D imaging of whole bone. In Aim 2, I will investigate the hypothesis that tumor cell interactions with the bone marrow niche control tumor cell phenotype via high dimensional spatial analysis of bone marrow biopsies from patients with breast cancer including imaging mass cytometry (IMC) and spatial single cell RNA sequencing (scRNAseq). In Aim 3, I will develop a biomaterial model of the dormant bone marrow niche via creating mechanical mimics of the three distinct compartments of bone marrow and evaluate the role of mechanosensing in induction and maintenance of dormancy. In the K99 phase of the award, Prof Max Wicha will serve as my main mentor. Dr. Wicha is a pioneer in the cancer stem cell field and is an expert in breast cancer biology and metastasis. I will work with and consult my collaborators and mentoring team, including Prof Fei Wen (imaging mass cytometry), Evan Keller (single cell spatial analysis program), Dr. Dafydd Thomas (pathology core), Prof Gary Luker (microscopy), Prof Monika Burness (breast cancer clinical oncology) and Prof Sofia Merjaver (breast cancer molecular biology). My K99 training will consist of developing a novel mouse model of bone marrow dormancy and learning bioinformatics approaches to analyze spatial contributions to cellular phenotype in IMC and scRNAseq data to propel me toward developing a synthetic dormant bone marrow niche mimic using biomaterials during the independent R00 phase. In sum, the proposed research will address an urgent, unmet need to identify the role of the bone marrow niche in breast cancer dormancy and reactivation, which may provide a path forward for identifying patients at higher risk of metastasis and developing therapies against reactivation.

项目概要/摘要 ER+乳腺癌患者在最初诊断数十年后可能会出现转移性复发。最丰胸癌症相关死亡是由转移引起的，因此可以识别高危患者并开发治疗方法防止重新激活是一项关键挑战。这些努力因缺乏了解而受到阻碍骨髓中的癌细胞休眠，被认为是转移复发的细胞根源。不太好了解肿瘤细胞如何与骨髓微环境相互作用以及这些相互作用如何调节肿瘤细胞的休眠和逃逸。我提出的研究旨在开发一种休眠和研究指导 K99 阶段患者样本中骨髓生态位的空间组织开发独立 R00 阶段休眠的生物材料模型。我假设 (i) 癌症干细胞是导致转移性复发的播散性肿瘤细胞子集和 (ii) 骨髓生态位，包括健康的干细胞生态位有助于这些细胞的休眠和重新激活。在目标 1 中，我将创作一部小说激素反应性乳腺癌在骨髓中休眠的小鼠模型并评估其存在，使用光学组织透明/3D 对播散性肿瘤细胞的表型和微环境调节全骨成像。在目标 2 中，我将研究肿瘤细胞与骨髓相互作用的假设通过对患者骨髓活检进行高维空间分析来控制肿瘤细胞表型乳腺癌，包括成像质谱流式分析 (IMC) 和空间单细胞 RNA 测序 (scRNAseq)。在目标 3 中，我将通过创建机械模拟来开发休眠骨髓生态位的生物材料模型骨髓的三个不同的隔室，并评估机械传感在诱导和治疗中的作用休眠的维持。在K99阶段的奖项中，Max Wicha教授将担任我的主要导师。博士。 Wicha是癌症干细胞领域的先驱，也是乳腺癌生物学和转移方面的专家。我会与我的合作者和指导团队一起工作并咨询他们，包括文飞教授（成像质谱流式细胞术）， Evan Keller（单细胞空间分析程序）、Dafydd Thomas 博士（病理学核心）、Gary Luker 教授（显微镜）、Monika Burness 教授（乳腺癌临床肿瘤学）和 Sofia Merjaver 教授（乳腺癌）分子生物学）。我的 K99 培训将包括开发一种新型骨髓休眠小鼠模型学习生物信息学方法来分析 IMC 和细胞表型的空间贡献 scRNAseq 数据推动我开发一种合成的休眠骨髓生态位模拟物独立R00阶段的生物材料。总之，拟议的研究将解决一个紧迫的、未满足的问题需要确定骨髓微环境在乳腺癌休眠和再激活中的作用，这可能提供识别转移风险较高的患者并开发针对再激活的疗法的前进之路。