Harnessing human brain and liver microphysiological systems for testing therapeutics for metastatic melanoma

项目概要 评估药物治疗转移性黑色素瘤有效性的标准是患者的反应， 但临床迫切需要一种可以支持药物疗效预测的人类替代模型， 从而使患者免于反复试验治疗，这最终将成为治疗的指南 选择针对患者的靶向药物治疗。如今，人们对使用源自患者的 异种移植（PDX），将患者的肿瘤植入免疫缺陷小鼠体内，以在 小鼠是患者肿瘤的模型。不幸的是，这个过程缓慢且昂贵，并且基于 动物微环境而不是人类微环境。微生理系统（MPS），包括 器官芯片、组织芯片和工程类器官可以使用人体细胞构建 体外微环境。拟议的研究将建立在范德比尔特大学的强有力合作基础上 大学、匹兹堡大学和威斯康星大学开发强大的 MPS 来解决 需要建立患者对癌症治疗反应的模型。该项目将研究组织如何 微环境通过使用微环境影响转移性黑色素瘤细胞的生长及其对药物的反应 范德比尔特神经血管单元组织芯片、匹兹堡肝脏芯片和威斯康星州工程类器官 对于大脑和肝脏，每个都包含多种细胞类型。研究将集中在最后阶段 转移级联反应——肿瘤细胞在远离原发肿瘤的部位生长。这种增长受到控制 通过肿瘤“种子”和组织微环境“土壤”之间的“种子和土壤”相互作用。而不是 以小鼠为土壤，将患者的癌细胞种植到MPS大脑和肝脏提供的土壤中 源自人类诱导多能干细胞的构建体。目标是 1) 实施一套通用的 人体器官构建体（芯片上的肝脏、神经血管单元和来自单个人体干细胞的工程类器官 细胞来源），2）证明这些人体器官构建体与转移性皮肤成功播种 来自范德比尔特和匹兹堡患者的黑色素瘤或葡萄膜黑色素瘤细胞，以及 3) 比较 植入器官芯片并经过改造的患者癌细胞对药物的反应 现有 PDX 系对相同药物有反应的类器官。该项目将提供以下方面的指导： 当转化为临床时，哪种体外人体模型可能更能预测患者的结果，基于 部分取决于肿瘤类型、患者样本的性质和患者基因型。它还将测试 假设范德比尔特、匹兹堡和威斯康星州开发的人类 MPS 设备和模型将 为研究肿瘤转移提供更真实的体外三维人体微环境 小鼠 PDX。最后阶段将是精准医学的概念验证演示，其中 大脑和肝脏的微环境可能来自患者的诱导多能干细胞。

Project Summary The standard for assessing the effectiveness of drugs to treat metastatic melanoma is the patient's response, but there is a pressing clinical need for a human surrogate model that could support prediction of drug efficacy, thereby saving the patient from trial and error treatments, and that would ultimately serve as a guide for the selection of patient-targeted drug therapies. Today, there is significant interest in the use of patient-derived xenografts (PDXs), in which a patient's tumor is implanted into an immune-deficient mouse, to create in the mouse a model of the patient's tumor. Unfortunately, this process is slow and expensive and is based upon an animal microenvironment rather than a human one. Microphysiological systems (MPS), which encompass organs-on-chips, tissue chips, and engineered organoids, can be constructed using human cells to create an in vitro microenvironment. The proposed research would build upon a strong collaboration at Vanderbilt University, the University of Pittsburgh, and the University of Wisconsin to develop powerful MPS to address the need for models of a patient's response to cancer therapy. This project will study how the tissue microenvironment affects the growth of metastatic melanoma cells and their response to drugs by using the Vanderbilt neurovascular unit tissue chip, the Pittsburgh liver-on-chip, and the Wisconsin engineered organoids for brain and liver, each of which includes multiple cell types. The research will focus on the final stage in the metastatic cascade – the growth of tumor cells at sites distant from the primary tumor. This growth is governed by “seed and soil” interaction between the tumor “seed” and the tissue microenvironment “soil.” Instead of using a mouse as the soil, patients' cancer cells will be planted into the soil provided by brain and liver MPS constructs derived from human induced pluripotent stem cells. The aims are 1) Implement a common set of human organ constructs (liver-on-chip, neurovascular unit, and engineered organoid from a single human stem cell source), 2) Demonstrate successful seeding of these human organ constructs with metastatic cutaneous melanoma or uveal melanoma cells derived from Vanderbilt and Pittsburgh patients, and 3) Compare the response to drugs by patients' cancer cells that have been seeded into the organs-on-chips and engineered organoids with the response to the same drugs by existing PDX lines. This project will provide guidance as to which in vitro human model might be more predictive of patient outcome when translated to the clinic, based in part upon the type of tumor, the nature of the patient sample, and the patient genotype. It will also test the hypothesis that the human MPS devices and models developed at Vanderbilt, Pittsburgh, and Wisconsin will provide a more realistic, in vitro, three-dimensional human microenvironment to study tumor metastasis than mouse PDXs. The final phase will be a proof-of-concept demonstration of precision medicine in which the microenvironment of the brain and liver could be from the patient's induced pluripotent stem cells.