Stroma-mediated clonal evolution in Multiple Myeloma

多发性骨髓瘤中基质介导的克隆进化

• 批准号: 8760768
• 负责人: Irene M. Ghobrial
• 金额: $ 35.38万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-07 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760768
• 关键词: Amino Acids; Applications Grants; Architecture; Automobile Driving; Benign; Biography; Biological Models; Biology; Blood Circulation; Bone Marrow; CXCL12 gene; Cancer Biology; Cells; Clonal Evolution; Complex; Data; Diagnosis; Disease; Disease Progression; Drug resistance; Event; Evolution; Feedback; Genes; Genetic; Genetic Transcription; Genome; Genomics; Grant; Growth; Heterogeneity; High Dose Chemotherapy; Homing; In Vitro; Lead; Malignant - descriptor; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchymal Cell Neoplasm; Messenger RNA; Methods; MicroRNAs; Modeling; Molecular; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mutation; Neoplasm Metastasis; Organ; Patients; Plasma Cells; Play; Point Mutation; Preparation; Publications; Regulation; Role; Sampling; Somatic Cell; Staging; Stem cell transplant; Stromal Cell-Derived Factor 1; Stromal Cells; Technology; Therapeutic; Time; Tumor-Derived; base; bone; cancer genomics; chemokine; deep sequencing; fluorophore; gain of function; in vivo; in vivo Model; in vivo imaging; inhibitor/antagonist; innovation; mouse model; neoplastic cell; novel; public health relevance; response; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is a disease of plasma cells with specific localization in the bone marrow. Recent studies in several malignancies including MM have shown intraclonal architectural heterogeneity at diagnosis and at different stages of disease progression over time. The presence of "clonal tides" in MM represent a novel paradigm in myeloma evolutionary biology which will revolutionize the current modeling of MM tumorigenesis and progression and are likely to have profound therapeutic implications. However, the role of the supporting bone marrow niche, specifically mesenchymal stromal cells (MSCs) in the clonal evolution of MM and other malignancies has not been previously elucidated. Although many factors regulating tumor progression are tumor cell autonomous, they are insufficient to induce progression and metastasis, and a permissive microenvironment is required for frank malignancy to emerge. In this grant, we focus on MSCs as critical regulators of clonal evolution in MM that allows for more rapid dissemination and drug resistance during disease progression. Our overarching hypothesis is that MSCs are integral regulators of clonal evolution in MM inducing both tumor dissemination and drug resistance during progression. We will examine this in 3 Specific Aims. Specific Aim 1 will elucidate sequential molecular events that occur in MSCs during MM progression and explore mechanisms of cooperativity of these events with tumor clonal evolution. MM patient samples at different stages of disease progression (MGUS to MM) will be used to determine molecular changes that occur in MSCs that correlate with, or drive tumor clonal diversification. Specific Aim 2 will determine the role of MSCs in clonal evolution in MM that leads to disease progression. The hypothesis of this aim is that MSCs confer selective advantage of specific clones for tumor progression in MM. We will use in vivo tracking of clones distinguished by fluorophores, where clonal subsets can be molecularly interrogated sequentially to track the biography of cells that emerge as "winner" or "loser" MM clones in response to loss-of or gain-of-function studies of specific genes deregulated in MSCs. Specific Aim 3 will investigate the role of the MSCs in the regulation of drug resistance in MM. Our hypothesis is that specific molecular changes that occur in MSCs after high-dose chemotherapy allow outgrowth of aggressive drug-resistant subclones of MM. In this aim, we will use in vitro and in vivo model systems to determine molecular changes that occur in MSCs after high dose chemotherapy used in stem cell transplant in MM and investigate how this in turn plays a role in clonal evolution and drug resistance in MM. This grant is focused on using innovative and diverse methods to understand the role of MSCs in clonal evolution in MM. We combine patient samples with mouse models to examine, in high-throughput unbiased methods, the role of MSCs in inducing tumor growth, clonal heterogeneity and drug resistance.

描述（由申请人提供）：多发性骨髓瘤（MM）是一种浆细胞特异性定位于骨髓的疾病。最近对包括多发性骨髓瘤在内的几种恶性肿瘤的研究表明，在诊断时和疾病随时间进展的不同阶段存在克隆内结构异质性。 MM 中“克隆潮”的存在代表了骨髓瘤进化生物学的一个新范式，它将彻底改变目前 MM 肿瘤发生和进展的模型，并可能具有深远的治疗意义。然而，支持性骨髓生态位，特别是间充质基质细胞 (MSC) 在多发性骨髓瘤和其他恶性肿瘤的克隆进化中的作用尚未阐明。尽管许多调节肿瘤进展的因素是肿瘤细胞自主的，但它们不足以诱导进展和转移，并且明显的恶性肿瘤的出现需要宽松的微环境。在这笔资助中，我们重点关注间充质干细胞作为多发性骨髓瘤克隆进化的关键调节因子，它可以在疾病进展过程中实现更快速的传播和耐药性。我们的总体假设是，间充质干细胞是多发性骨髓瘤克隆进化的整体调节因子，在进展过程中诱导肿瘤播散和耐药性。我们将在 3 个具体目标中对此进行研究。具体目标 1 将阐明 MM 进展过程中 MSC 中发生的连续分子事件，并探索这些事件与肿瘤克隆进化的协同机制。处于疾病进展不同阶段（MGUS 到 MM）的 MM 患者样本将用于确定 MSC 中发生的与肿瘤克隆多样化相关或驱动肿瘤克隆多样化的分子变化。具体目标 2 将确定 MSC 在导致疾病进展的 MM 克隆进化中的作用。这一目标的假设是 MSC 赋予特定克隆对 MM 肿瘤进展的选择性优势。我们将使用通过荧光团区分的克隆的体内追踪，其中克隆子集可以按顺序进行分子询问，以追踪因功能丧失或获得而作为“获胜者”或“失败者”MM克隆出现的细胞的传记间充质干细胞中特定基因失调的研究。具体目标 3 将研究 MSC 在调节 MM 耐药性中的作用。我们的假设是，高剂量化疗后 MSC 中发生的特定分子变化使得侵袭性耐药的 MM 亚克隆得以生长。为此，我们将使用体外和体内模型系统来确定 MM 干细胞移植中使用的高剂量化疗后 MSC 中发生的分子变化，并研究其如何在 MM 的克隆进化和耐药性中发挥作用。该资助的重点是使用创新和多样化的方法来了解 MSC 在 MM 克隆进化中的作用。我们将患者样本与小鼠模型相结合，以高通量无偏见的方法检查 MSC 在诱导肿瘤生长、克隆异质性和耐药性中的作用。