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。

• 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
• 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

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.

项目摘要 /摘要 原始诊断后数十年的ER+乳腺癌患者可能发生转移性复发。大多数乳房 与癌症相关的死亡是由转移引起的，因此鉴定出高危患者并开发疗法 防止重新激活是至关重要的挑战。这些努力受到了对 骨髓中的癌细胞休眠，被认为是转移性复发的细胞来源。不好 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 肿瘤细胞休眠和逃生。我提出的研究旨在开发一个休眠和 研究指导的K99期和 在独立的R00相中开发休眠的生物材料模型。我假设（I）癌症干细胞是 负责转移性复发和（ii）骨髓生态位的一部分散布肿瘤细胞，包括 健康的干细胞生态位促进了这些细胞的休眠和重新激活。在AIM 1中，我将开发一本小说 骨髓中激素反应性乳腺癌休眠的小鼠模型，并评估存在 使用光学组织清除/3D对散布肿瘤细胞的表型和微环境调节 整个骨头的成像。在AIM 2中，我将研究肿瘤细胞与骨髓相互作用的假设 利基控制肿瘤细胞表型通过对患者的骨髓活检的高维空间分析 乳腺癌包括成像质量细胞术（IMC）和空间单细胞RNA测序（SCRNASEQ）。 在AIM 3中，我将通过创建机械模拟 在骨髓的三个不同隔室中，并评估了机械感应在诱导和 维持休眠。在该奖项的K99阶段，Max Wicha教授将担任我的主要导师。博士 WICHA是癌症干细胞场的先驱，并且是乳腺癌生物学和转移的专家。我会 与我的合作者和指导团队合作，包括Fei Wen教授（成像质量细胞仪）， 埃文·凯勒（Evan Keller）（单细胞空间分析计划），Dafydd Thomas博士（病理核心），Gary Luker教授 （显微镜），Monika Burness教授（乳腺癌临床肿瘤学）和索非亚教授（乳腺癌） 分子生物学）。我的K99训练将包括开发新型的骨髓休眠模型 以及学习生物信息学方法，分析了IMC和IMC中细胞表型的空间贡献 scrnaseq数据推动我使用合成性休眠的骨髓小裂模拟 在独立R00期间的生物材料。总而言之，拟议的研究将解决紧急，未得到满足的问题 需要确定骨髓生态位在乳腺癌休眠和重新激活中的作用，这可能会提供 识别出较高转移风险和开发反应疗法的患者的前进道路。