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）是一种在骨髓中特异性定位的浆细胞疾病。最近在包括MM在内的几种恶性肿瘤的研究表明，随着时间的推移，诊断和疾病进展的不同阶段的隆内结构异质性。 MM中“克隆潮汐”的存在代表了骨髓瘤进化生物学中的一种新型范式，该范式将彻底改变MM肿瘤发生和进展的当前建模，并可能具有深远的治疗意义。然而，支撑骨髓生态位的作用，特别是间充质基质细胞（MSC）在MM和其他恶性肿瘤的克隆进化中的作用。尽管调节肿瘤进展的许多因素是肿瘤细胞自主的，但它们不足以诱导进展和转移，并且坦率的恶性肿瘤需要宽松的微环境。在这笔赠款中，我们专注于MSC作为MM克隆进化的关键调节剂，从而使疾病进展过程中更快地传播和耐药性。我们的总体假设是，MSC是MM克隆进化不可或缺的调节剂，在进展过程中诱导肿瘤传播和耐药性。我们将在3个具体目标中进行研究。具体目标1将阐明MM进展过程中MSC中发生的顺序分子事件，并探索这些事件随肿瘤克隆进化的合作机制。 MM患者样本在疾病进展的不同阶段（MGS至mm）将用于确定与肿瘤克隆多样化相关或驱动肿瘤克量多样化的MSC中发生的分子变化。具体目标2将确定MSC在MM克隆进化中的作用，从而导致疾病进展。该目标的假设是MSC赋予特定克隆在MM中的肿瘤进展的选择性优势。我们将使用由荧光团区分的克隆的体内跟踪，可以对克隆子集进行分子询问，以依次询问克隆子集，以跟踪出现为“获胜者”或“失败者” MM克隆的细胞的传记，以响应于MSC中特定基因的功能丧失或功能性研究。具体目标3将研究MSC在MM中耐药性调节中的作用。我们的假设是，高剂量化学疗法后MSC中发生的特定分子变化允许MM的抗药性亚克隆生长。在此目标中，我们将使用体外和体内模型系统来确定在MM中使用的高剂量化学疗法后MSC中发生的分子变化，并研究它在MM中如何在克隆进化和耐药性中发挥作用。该赠款的重点是使用创新和多样化的方法来了解MSC在MM中克隆进化中的作用。我们将患者样品与小鼠模型相结合，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。