(PQB6)An Integrative Computational and Bioengineered Tissue Model of Metastasis

描述（由申请人提供）：转移性癌症生长是癌症治疗中最具挑战性的领域之一。 然而，转移是很难系统地研究， 这主要是由于细胞培养模型和体内肿瘤生长之间的差异。 许多研究致力于定义肿瘤进展过程中的分子和生化变化，但更深入地了解癌细胞与器官微环境之间的相互作用对癌症治疗的未来进展至关重要。 我们的总体目标是开发一个综合的生物工程/计算模型的转移性肿瘤生长，以探讨生长动力学，异质性微环境和基础生物物理学之间的关系。 该提案通过直接合并物理科学，再生医学和组织工程的方法，应用跨学科的方法来治疗癌症转移。 南加州大学领导的多机构团队开发了复杂虚拟组织中血管化肿瘤生长的机械，多尺度计算模型。 维克森林大学开发了组织生物工程技术，以创建功能性肝脏类器官，这些类器官可以注射癌细胞，并将用于重现癌症转移的体内环境。 我们建议使用生物工程来原位创建具有人类肝脏天然结构和功能的活肝组织。 所提出的集成生物工程/计算平台应提供前所未有的时空分辨率和转移性结肠癌生长的微环境控制。 在本提案的目标1中，计算模型将根据生物工程肝盘和原位类器官实验的数据进行校准。 结肠癌转移发展的模拟预测将与实验进行比较，以量化准确性并确定模型改进的需要。 在目标2中，校准模型将用于系统地研究不同微环境条件下的结肠肿瘤生长动力学，其中我们通过施加机械力、改变氧合和给予治疗来调节生物物理参数。 我们将在这些相同的条件下验证模型的预测对原位类器官实验。 在目标3中，我们将根据患者来源的转移性结肠肿瘤外植体校准模拟器，并确定肿瘤生长的模拟是否与来自相同患者的成像和结果数据一致。 该项目将创建一个首创的综合计算/生物工程肝转移模型，提供一个可重复的，可控的系统，用于探测和操纵转移的动态，测试和完善假设，并做出可以外推到人类癌症的预测。 这些综合建模工作将为理解肿瘤扩散提供新的维度，并产生有关治疗癌症转移的重要信息。

DESCRIPTION (provided by applicant): Metastatic cancer growth is one of the most challenging areas in cancer treatment. However, metastasis is difficult to study systematically in the laboratory largely due to discrepancies between cell culture models and tumor growth in vivo. Much research has been devoted to defining molecular and biochemical changes during tumor progression, but a deeper understanding of the interaction between cancer cells and the organ microenvironment is crucial to future advances in cancer therapy. Our overall goal is to develop an integrated bioengineered/computational model of metastatic tumor growth to probe the relationships between growth dynamics, heterogeneous microenvironments, and the underlying biophysics. This proposal applies an interdisciplinary approach to cancer metastasis by directly merging the methods of the physical sciences, regenerative medicine, and tissue engineering. A University of Southern California-led multi-institutional team has developed mechanistic, multiscale computational models of vascularized tumor growth in complex virtual tissues. Wake Forest University has developed tissue bioengineering techniques to create functional liver organoids that can be injected with cancer cells and will be used to recapitulate the in vivo milieu of cancer metastasis. We propose to use bioengineering to create living liver tissues in situ with the native structure and function of human livers. The proposed integrated bioengineered/computational platform should give unprecedented spatiotemporal resolution and microenvironmental control of metastatic colon cancer growth. In Aim 1 of this proposal the computational model will be calibrated to data from bioengineered hepatic disc and in situ organoid experiments. Simulation predictions of colon cancer metastatic development will be compared to experiments to quantify accuracy and determine need for model refinements. In Aim 2, the calibrated model will be used to systematically investigate colon tumor growth dynamics under diverse microenvironmental conditions, in which we modulate biophysical parameters by applying mechanical forces, altering oxygenation, and administering therapeutics. We will validate the model's predictions against in situ organoid experiments under these same conditions. In Aim 3, we will calibrate the simulator to patient-derived metastatic colon tumor explants and determine if simulations of tumor growth correspond with imaging and outcome data from the same patients. This project will create a first-of-its-kind integrated computational/bioengineered liver metastasis model, providing a reproducible, controllable system for probing and manipulating the dynamics of metastasis, testing and refining hypotheses, and making predictions that can be extrapolated to human cancer. These integrative modeling efforts will give a new dimension to understanding tumor spread and yield important information about treating cancer metastases.