Mechano-regulation of bone metastatic cancer: linking cell strain to cell function

PI：林奇，莫林。转移性癌症向骨骼扩散是常见的，转移发生后，由于严重的骨骼相关并发症，包括骨破坏（“骨溶解”），患者预后急剧下降。该项目的目标是首次定义由身体活动产生的机械信号，这是骨细胞功能和重塑的主要调节剂，如何调节暴露于相同信号的骨转移细胞。这将通过追求三个目标来实现：1)在三维骨模拟支架中建立组织级机械载荷的多物理场计算模型。2)确定骨转移性乳腺癌细胞与流体相互作用产生的细胞株，3)定义细胞株与骨转移性乳腺癌细胞溶骨表型之间的数据驱动关系。该结果将改变对肿瘤细胞如何在骨骼微环境中受到调节的基本理解，具有改善该疾病临床管理的巨大潜力。通过增加本科阶段生物工程的教育机会，让马萨诸塞大学未被充分代表的初中和高中人口参与生物工程研究，积极招募未被充分代表的群体的研究生，扩大生物工程领域的参与，将实现教育影响。该奖项由数学科学部的计算数学项目通过BioMaPs项目共同资助。该项目旨在首次定义一种连接转移性癌细胞功能和细胞变形的机械调节算法。骨骼是许多癌症转移的首选部位，包括乳腺癌、前列腺癌、肺癌和肾癌。转移发生后，由于严重的骨骼相关并发症，包括骨破坏（骨溶解），患者预后急剧下降。身体活动产生的机械信号是骨细胞功能和重塑的主要调节因子，骨转移细胞也暴露于这些信号；然而，它们在转移中的作用尚不清楚，因为它们在转移性骨病的研究中经常被忽视。以乳腺癌为例，我们的初步数据显示，在3D骨模拟支架中压缩骨转移肿瘤细胞改变了其修饰骨重塑的基因表达，支持我们的假设，即骨骼机械信号是肿瘤细胞行为的基本调节因子。在这里，我们试图通过开发一个集成的体外3D实验和多物理场，多尺度计算平台，系统地定义机械信号和骨转移细胞功能之间的功能关系。该项目将受益于体外加载工程系统和癌症生物学以及计算流体结构建模专家之间的合作。本研究计划有三个目标：1)在我们的三维骨模拟支架中建立组织级机械载荷的多物理场计算模型。方法：本目标将生成一个“组织水平”的计算模型，包括有限元和计算流体动力学分析，以确定我们的骨支架在压缩和灌注过程中的内应力和应变。将支架的MicroCT图像转换为离散模型，并基于单向耦合方法计算支架内诱导流速和细胞外基质应变的估计值；2)确定骨转移乳腺癌细胞与液体流动相互作用产生的细胞株。方法：这个目标将创建一个“细胞水平”的细胞变形计算模型。利用目标1的内部流速和牵引力估计值作为全耦合流固耦合算法的边界条件，该算法将用于模拟支架间流体流动与癌细胞之间的相互作用；3)定义细胞株与骨转移性乳腺癌细胞溶骨表型之间的数据驱动关系。方法：这一目标将导致一个数据驱动的机械调节算法骨转移乳腺癌细胞。首先，在骨支架中培养的肿瘤细胞在一系列施加的机械负荷环境下的细胞反应将通过溶骨基因的表达来测量。这些结果将在数学上与目标2中使用多元统计分析的细胞变形相关。该项目的结果将改变我们对肿瘤细胞如何在骨骼微环境中受到调节的基本理解，具有改善该疾病临床管理的巨大潜力。从这些研究中收集的数据将为确定机械刺激在骨转移中的作用奠定基础。通过增加本科阶段生物工程的教育机会，让马萨诸塞大学未被充分代表的初中和高中人口参与生物工程研究，积极招募未被充分代表的群体的研究生，扩大生物工程领域的参与，将实现教育影响。

PI: Lynch, Maureen. Proposal #: 1605060 Metastatic cancer spread to the skeleton is common and after the metastasis occurs, patient prognosis dramatically declines due to severe skeletal-related complications, including bone destruction ("osteolysis"). The goal of this project is to define for the first time how the mechanical signals arising from physical activity, which are the primary regulator of bone cell function and remodeling, regulate the bone metastatic cells that are exposed to the same signals. This will be accomplished by pursuing three objectives: 1) Building a tissue-level multi-physics computational model of mechanical loading in a 3D bone mimetic scaffold. 2) Determining the cellular strains resulting from interactions between bone metastatic breast cancer cells and fluid flow and 3) defining a data-driven relationship between cellular strains and bone metastatic breast cancer cell osteolytic phenotype. The results will transform fundamental understanding of how tumor cells are regulated in the skeletal microenvironment with considerable potential to improve clinical management of the disease. Educational Impact will be achieved through increased educational opportunities in bioengineering at the undergraduate level, engage middle and high school underrepresented populations in bioengineering research at UMass, and active recruitment of graduate students from underrepresented groups to broaden participation in the field of bioengineering. This award is cofunded by the Computational Mathematics program in the Division of Mathematical Sciences through the BioMaPs program. This project seeks to define, for the first time, a mechano-regulatory algorithm that links metastatic cancer cell function and cellular deformations. The skeleton is the preferred site for metastasis in many cancers, including breast, prostate, lung, and kidney. After metastasis occurs, patient prognosis dramatically declines due to severe skeletal-related complications, including bone destruction (?osteolysis?). Mechanical signals arising from physical activity are the primary regulator of bone cell function and remodeling, and bone metastatic cells are also exposed to these signals; however, their role in metastasis in unclear because they are often ignored in studies of metastatic bone disease. Using breast cancer as our example case, our preliminary data shows that compression of bone metastatic tumor cells in a 3D bone mimetic scaffold altered their expression of genes that modify bone remodeling, supporting our hypothesis that skeletal mechanical signals are a fundamental regulator of tumor cell behavior. Here, we seek to systematically define the functional relationship between mechanical signals and bone metastatic cell function through development of an integrated in vitro 3D experimental and multi-physics, multi-scale computational platform. This project will benefit from collaboration between experts in engineered systems of in vitro loading and cancer biology as well as computational fluid-structure modeling. The Research Plan is presented as three objectives: 1) Build a tissue-level multi-physics computational model of mechanical loading in our 3D bone mimetic scaffold. Method: This objective will generate a "tissue-level" computational model including Finite Element and Computational Fluid Dynamic analysis to determine the internal stresses and strains of our bone scaffold undergoing compression and perfusion. MicroCT images of the scaffold will be converted to a discretized model, and estimated values of the induced flow velocities and the extracellular matrix strain within the scaffold will be calculated based on a one-way coupling method; 2) Determine the cellular strains resulting from interactions between bone metastatic breast cancer cells and fluid flow. Method: This objective will create a "cell-level" computational model of cellular deformations. The estimated values of internal flow velocity and tractions from Objective 1 are utilized as the boundary conditions for a fully-coupled Fluid-Structure Interaction algorithm, which will be used to model the interaction between the inter-scaffold fluid flow and cancer cells; 3) Define a data-driven relationship between cellular strains and bone metastatic breast cancer cell osteolytic phenotype. Method: This objective will result in a data-driven mechano-regulatory algorithm for bone metastatic breast cancer cells. First, the cellular response of tumor cells, cultured in our bone scaffold, under a range of imposed mechanical loading environments will be measured via expression of osteolytic genes. These results will be mathematically correlated to the cellular deformations from Objective 2 using multivariate statistical analysis. The results of this project will transform our fundamental understanding of how tumor cells are regulated in the skeletal microenvironment with considerable potential to improve clinical management of the disease. The data collected from these studies will form the foundation for defining the role of mechanical stimulation during bone metastasis. Educational Impact will be achieved through increased educational opportunities in bioengineering at the undergraduate level, engage middle and high school underrepresented populations in bioengineering research at UMass, and active recruitment of graduate students from underrepresented groups to broaden participation in the field of bioengineering.