Modelling the Growth of the MIC Niche at the System Level

描述（由申请人提供）：目标是开发连贯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（BMSCs，也称为骨髓衍生间充质干细胞）之间调节MIC进化的生物力学相互作用。为此，我们将研究癌症干细胞生态位（微环境）的生物物理特性和信号通路，最终目标是建立MM癌症生长模型，以预测针对生态位的新治疗策略。尽管多发性骨髓瘤（MM）患者在使用目前可用的治疗药物后最初可能达到完全缓解，但大多数MM患者最终会复发。研究表明，在这些患者中存在一小部分具有克隆潜能和高耐药性的MICs。我们的初步研究得出以下假设：1) mic分泌高浓度的SDF1，激活SDF1/CXCR4信号通路，导致BMSCs生物力学表型的改变；2)改变的BMSCs力学特性影响mic的命运（增殖和存活），从而影响MM的生长。CXCR4是一种g蛋白偶联受体，是肌动蛋白/肌球蛋白依赖的细胞骨架信号过程的控制点，从而调节细胞膜力学。本研究的目标是更全面地描述SDF1/CXCR4信号通路如何影响骨髓瘤骨髓间充质干细胞的力学特性，并通过新的数学模型建模和预测这种变化对MIC命运的影响。提出了一种预测的基于三维多尺度agent的模型（ABM）来研究肿瘤-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相关骨髓间充质干细胞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：细胞间相互作用是连接MIC和BMSC的细胞内特征与MIC、BMSC以及祖细胞（PCs）和MM的细胞内生物力学表型转换的枢纽链。(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。为了实现我们的目标，

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.