Multiscale Modeling of Bone Environment Responses to Metastatic Prostate Cancer

 描述(申请人提供)：骨转移性前列腺癌是致命的，分别通过操纵成骨细胞和破骨细胞导致广泛的病理性骨生长和破坏。了解导致这种疾病的因素有助于确定新的治疗靶点。实验方法已经剖析了许多涉及的分子机制，但随着时间的推移，不同规模的因素如何共同影响复杂的多细胞相互作用是一个重大挑战。将分子、细胞和临床信息集成到计算模型中为克服这一障碍提供了一种新颖而有力的方法：来自不同尺度的细胞过程和机制可以被分解为离散和连续的组件，并用于对多尺度模型进行参数化。然后，该模型可用于研究多尺度细胞相互作用产生的时间动力学。理论基础：利用我们自己和发表的数据，我们建立了一个由转化生长因子β和RANKL控制的正常骨重建的新的计算模型。将在硅胶病变中产生的转移性前列腺癌细胞种植到模型中，这种细胞定性和定量地模拟了人类疾病的病理生理学。正如预期的那样，我们的初步模型证实了转化生长因子β的作用，但预测了周期性破骨细胞浸润和间充质干细胞在前列腺癌生长中的新作用。基于这些新出现的数据，我们相信，利用控制前列腺癌-骨相互作用的细胞和分子因素(PTHrP、WNTS、白细胞介素2、趋化因子和极化巨噬细胞)来增强计算模型，将使我们能够预测驱动骨转移性前列腺癌行为的关键电路，并定义治疗这种疾病的新治疗策略。我们将使用以下综合方法来验证这一假设：方法：在目标1中，将开发一个增强的分子和细胞多尺度计算模型，并将预测驱动骨转移癌生长的关键电路。在目标2中，我们将预测周期性破骨细胞浸润和巨噬细胞极化(M1/M2)在促进前列腺癌生长中的作用。目的3分析MSC募集在前列腺癌诱导成骨中的作用。重要的是，在每个目标中产生的预测将通过相关的骨转移性前列腺癌啮齿动物模型进行检验，并在人类临床标本中得到验证。在输出不一致的情况下，将使用定量生物学值来重新校准计算模型。创新/影响：我们的创新研究将：1)产生前列腺癌-骨微环境的强大和动态的多尺度计算模型；2)定义单核细胞衍生细胞(破骨细胞/M1/M2巨噬细胞)在推动前列腺癌生长中的新角色；3)定义MSCs在促进前列腺癌诱导成骨方面的新角色；4)预测驱动骨转移性前列腺癌的关键电路；5)预测和测试根除骨转移性前列腺癌的治疗策略。

 DESCRIPTION (provided by applicant): Bone metastatic prostate cancer is fatal and causes extensive pathological bone growth and destruction by manipulating osteoblasts and osteoclasts respectively. Understanding the factors driving the disease can help identify new therapeutic targets. Experimental approaches have dissected many of the molecular mechanisms involved but how factors at different scales collectively impact complex multi-cellular interactions over time is a significant challenge. Integrating molecular, cellular and clinical information into computational models offers a novel and powerful way to overcome this road-block: cell processes and mechanisms from different scales can be broken down into discrete and continuous components and used to parameterize a multi-scale model. This model can then be used to examine the temporal dynamics emerging from the multi scale cellular interactions. Rationale: Using our own and published data, we generated a novel computational model of normal bone remodeling controlled by TGFβ and RANKL. Seeding the model with a metastatic prostate cancer cell generated in silico lesions that qualitatively and quantitatively mimic the pathophysiology of the human disease. As expected, our preliminary model confirmed the role of TGFβ but predicted novel roles for cyclical osteoclast infiltration and mesenchymal stem cells in prostate cancer growth. Based on these emerging data, we believe that the enhancement of the computational model with cellular and molecular factors that control prostate cancer-bone interaction (PTHrP, Wnts, interleukins, chemokines and polarizing macrophages) will allow us to predict the key circuits driving the behavior of bone metastatic prostate cancer and to define new therapeutic strategies to treat this disease. We will test this hypothesis using the following integrated approaches: Approaches: In Aim 1, an enhanced molecular and cellular multiscale computational model will be developed and the key circuits driving bone metastatic cancer growth will be predicted. In Aim 2, we will predict the role of cyclical osteoclast infiltration and macrophage polarization (M1/M2) in promoting prostate cancer growth. Aim 3 will dissect the role of MSC recruitment in prostate cancer induced osteogenesis in silico. Importantly, the predictions generated in each aim will be tested with relevant in vivo rodent models of bone metastatic prostate cancer and validated in human clinical specimens. Quantitative biological values will be used to recalibrate the computational model in the event that outputs are discordant. Innovation/Impact: Our innovative studies will; 1) generate a robust and dynamic multi-scale computational model of the prostate cancer-bone microenvironment, 2) will define novel roles for monocyte derived cells (osteoclasts/M1/M2 macrophages) in driving prostate cancer growth, 3) will define new roles for MSCs in promoting prostate cancer induced osteogenesis, 4) will predict the key circuits driving bone metastatic prostate cancers and 5) will predict and test curative strategies for eradicating bone metastatic prostate cancer.