Modelling the Growth of the MIC Niche at the System Level

在系统级别对 MIC 利基的增长进行建模

• 批准号: 8460808
• 负责人: Xiaobo Zhou
• 金额: $ 41.48万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460808
• 关键词: AMD3100; Actins; Adherence; African American; American Cancer Society; Apoptosis; Autologous Stem Cell Transplantation; Biological Assay; Biological Models; Biomechanics; Bone Marrow; Bone Marrow Stem Cell; CXCR4 Signaling Pathway; CXCR4 gene; Cell Communication; Cell Lineage; Cell membrane; Cells; Cessation of life; Coculture Techniques; Computer Simulation; Data; Development; Diagnosis; Disease; Disease remission; Drug resistance; Evolution; Feedback; G-Protein-Coupled Receptors; Goals; Graph; Growth; Hematopoietic Neoplasms; High Dose Chemotherapy; Hydrogels; Lead; Link; Malignant Neoplasms; Mathematics; Measures; Mechanics; Mesenchymal Stem Cells; Modeling; Multiple Myeloma; Myosin ATPase; Outcome; Pathway interactions; Patients; Phenotype; Plasma Cells; Play; Population; Property; Protocols documentation; Publications; RNA Interference; Recurrent disease; Role; Signal Pathway; Signal Transduction; Stem cells; Stream; Stromal Cells; System; Therapeutic Agents; Tissues; United States; base; biological systems; cancer cell; cancer stem cell; cell type; computerized data processing; cytokine; improved; inhibitor/antagonist; mathematical model; novel; novel therapeutics; outcome forecast; research study; stem cell niche; tool; treatment response; tumorigenesis

DESCRIPTION (provided by applicant): The goal is to develop coherent experimental protocols and predictive mathematical models for understanding the biomechanical interaction between myeloma-initiating cells (MICs, also known as myeloma stem cells) and bone marrow stromal cells (BMSCs, also known as bone marrow derived mesenchymal stem cells) regulating the MIC evolution. To do so, we will study the biophysical properties and signaling pathways of cancer stem cell niches (microenvironments) with the ultimate goal of developing MM cancer growth models to predict new therapeutic strategies targeting the niches. Even though multiple myeloma (MM) patients may reach a complete remission initially with therapeutic agents currently available, most MM patients eventually developed relapsed disease. Studies have suggested the presence of a small population of MICs in these patients that possess clonogenic potential and high resistance to drugs. Our preliminary studies lead to the hypotheses: 1) that MICs secret a high concentration of SDF1 which activates the SDF1/CXCR4 signaling pathway, leading to the changes in biomechanical phenotype of BMSCs and consequently, 2) that the altered BMSC mechanical properties contribute to the fate (proliferation and survival) of MICs, and thus the growth of MM. CXCR4, a G-protein coupled receptor, constitutes a control point for actin/myosin-dependent cytoskeletal signaling processes and thus regulates cell and membrane mechanics. The goals of the proposed study are to more fully characterize how the mechanical properties of myeloma BMSCs are influenced by the SDF1/CXCR4 signaling pathway, and to model and predict the impact of such changes on MIC fate by novel mathematic models. A predictive 3D multi-scale agent-based model (ABM) is proposed to investigate the role of cancer - stroma cell-to-cell interactions in multi-myeloma tumorigenesis. It includes: (a) Intracellular level: The intracellular signaling pathway features of myeloma initiating cells (MICs) and MM associated BMSCs may dominate biomechanically induced MM cancer cell phenotypes at intercellular level, cancer development and disease prognosis in the tissue level. (b) Intercellula level: Cell-to-cell interactions are the pivot chain linking intracellular level features of MIC an BMSC to intracellular biomechanical phenotype switch of MIC, BMSC, and progenitor cells (PCs) and MM. And (c) Tissue level: The cytokines secreted from MIC, PC and MM in the tissue level will regulate the proliferation and differentiation of MICs. In order to implement our goals, we set the specific aims: 1) Establish signaling pathway system using Modulated Factor Graph in regulating MICs and BMSCs by evaluating if modifying the CXCR4/SDF1 pathway changes the biomechanical properties of BMSCs and if these changes influence the proliferation and survival of MICs. 2) Establish MIC lineage model by developing quantitative cellular and cytokine assays to measure the amounts of different types of cells and secretary stimulatory/inhibitory cytokines using the well defined biological system. 3) Establish the predictive 3D MM growth model using Agent-based Model (ABM) by incorporating the biomechanical signaling pathways at intracellular level and the cell-cell interactions at intercellular level. The modeling system established will provide us a critical tool to see how we can manipulate the biomechanical interaction to interrupt the MIC development, which leads to the cure of myelomas.

描述（由申请人提供）：目标是开发一致的实验方案和预测数学模型，以了解骨髓瘤起始细胞（MIC，也称为骨髓瘤干细胞）和骨髓基质细胞（BMSC，也称为骨髓源性间充质干细胞）之间调节MIC演变的生物力学相互作用。为此，我们将研究癌症干细胞小生境（微环境）的生物物理特性和信号通路，最终目标是开发MM癌症生长模型，以预测针对小生境的新治疗策略。尽管多发性骨髓瘤（MM）患者最初可使用目前可用的治疗药物达到完全缓解，但大多数MM患者最终会出现复发性疾病。研究表明，在这些患者中存在一小部分MIC，具有克隆形成潜力和对药物的高耐药性。我们的初步研究得出以下假设：1）MIC分泌高浓度的SDF 1，其激活SDF 1/CXCR 4信号通路，导致BMSC的生物力学表型的变化，并且因此，2）改变的BMSC机械性质有助于BMSC的命运，（增殖和存活），并因此促进MM. CXCR 4，一种G蛋白偶联受体，构成肌动蛋白/肌球蛋白依赖性细胞骨架信号传导过程的控制点，从而调节细胞和膜力学。 该研究的目的是更全面地表征骨髓瘤BMSCs的机械特性如何受到SDF 1/CXCR 4信号通路的影响，并通过新的数学模型建模和预测这些变化对MIC命运的影响。提出了一种预测性3D多尺度基于代理的模型（ABM）来研究癌症-基质细胞-细胞相互作用在多发性骨髓瘤肿瘤发生中的作用。它包括：（a）细胞内水平：骨髓瘤起始细胞（MIC）和MM相关BMSC的细胞内信号通路特征可能在细胞间水平上主导生物力学诱导的MM癌细胞表型，在组织水平上主导癌症发展和疾病预后。(b)细胞间水平：细胞-细胞相互作用是连接MIC和BMSC的细胞内水平特征与MIC、BMSC、祖细胞（PC）和MM的细胞内生物力学表型转换的枢轴链。（c）组织水平：MIC、PC和MM在组织水平分泌的细胞因子将调节MIC的增殖和分化。 我们设定了具体目标：1）通过评估修饰CXCR 4/SDF 1通路是否改变BMSCs的生物力学特性以及这些改变是否影响MIC的增殖和存活，使用调节因子图建立调节MIC和BMSCs的信号通路系统。2）通过发展定量细胞和细胞因子测定来测量不同类型细胞和分泌刺激因子的量，建立MIC谱系模型。抑制性细胞因子使用明确定义的生物系统。3)通过引入细胞内水平的生物力学信号通路和细胞间水平的细胞-细胞相互作用，使用基于Agent的模型（ABM）建立预测性3D MM生长模型。建立的模型系统将为我们提供一个关键的工具，看看我们如何能够操纵生物力学的相互作用，中断MIC的发展，从而导致骨髓瘤的治愈。