Supramolecular matrix materials for prostate cancer cell biology

前列腺癌的发病率和死亡率仍然是重要的临床问题，而前列腺癌的发展 新的治疗策略取决于提高我们对前列腺癌生物学的基本理解。是这样的 基础研究反过来又依赖于准确和相关的实验模型，包括体外和 在活体内。然而，前列腺癌的基础研究受到了难以确定患者的挑战。 衍生的细胞系和缺乏充分定制的3D细胞培养基质。目前， 大多数人的前列腺癌细胞系来自于耐去势转移，并且在 与胰腺癌等其他癌症相比，高级别前列腺癌起源于临床 标本在动物模型中不能有效地建立为异种移植物。当前3D细胞培养基质 例如Matrigel已经使该领域建立了一些前列腺癌有机培养物，但Matrigel的 其有效性受到批次间一致性差以及难以调整其组成的限制 特定单元格类型和特定上下文。因此，开发了更多定义和可定制的矩阵 将克服在建立和维护前列腺癌细胞器官方面的主要技术障碍 基础研究。Collier实验室最近开发了一种策略，可以从定义的几组 表达的蛋白质，使用分子自组装。在这种方法中，蛋白质被设计成显示一个 允许细菌学在单体状态下表达但随后自组装成 定义了与短合成多肽混合后的3D培养基质。这些材料可以配制成 制成成分定义的细胞培养材料，使我们能够在拟议的工作中改进工程 支持前列腺癌有机物生长的3D培养介质。这项工作将通过两个阶段进行 目标如下。目的1：研制适合前列腺癌细胞体外生长的细胞培养基质 体内肿瘤启动，使用新的自组装蛋白(β-Tail)和自组装肽。 目标2：开发前列腺特异性抗原(PSA)反应的3D培养液，并将其改造为 原代人前列腺细胞分泌PSA时释放FGF10，从而加速细胞生长。我们 期望这些可定制的细胞培养基质不仅用于培养患者来源的 前列腺癌细胞，也可用于多种额外的细胞类型。这个项目将是一个关键的 概念验证，将为这些材料在一系列未来的开发奠定基础 不同的文化背景。科利尔博士和范德·格里德博士这两名私家侦探是在 部门(外科)，促进这一合作，旨在解决长期存在的不合适的问题 前列腺器官培养基质。

Prostate cancer incidence and mortality continue to be significant clinical problems, and the development of new treatment strategies depends on improving our basic understanding of prostate cancer biology. Such basic investigations in turn are dependent on accurate and relevant experimental models, both in vitro and in vivo. However, basic prostate cancer research has been challenged by difficulties in establishing patient- derived cell lines and the unavailability of adequately tailored 3D cell culture matrices. Currently, the majority of human prostate cancer cell lines are derived from castration-resistant metastases, and in contrast to other cancers such as pancreatic cancer, high-grade prostate tumors derived from clinical specimens do not efficiently establish in animal models as xenografts. Current 3D cell culture matrices such as Matrigel have enabled the field to establish some prostate cancer organoid cultures, but Matrigel’s usefulness is limited by its poor batch-to-batch consistency and difficulties in adjusting its composition for specific cell types and specific contexts. Thus, the development of more defined and customizable matrices would overcome a major technical hurdle in establishing and maintaining prostate cancer cell organoids for basic study. The Collier lab has recently developed a strategy for creating gel materials from defined sets of expressed proteins, using molecular self-assembly. In this approach, proteins are engineered to display a novel tag that allows bacteriologic expression in a monomeric state, but subsequent self-assembly into defined 3D culture matrices upon mixing with short synthetic peptides. These materials can be formulated into compositionally defined cell culture materials, allowing us in the proposed work to engineer improved 3D culture media that support prostate cancer organoid growth. The work will be conducted through two aims, as follows. Aim 1: Develop a tailored cell culture matrix for prostate cancer cell growth in vitro and tumor initiation in vivo, using novel self-assembling proteins (beta-Tails) and self-assembling peptides. Aim 2: Develop prostate-specific antigen (PSA)-responsive 3D culture media and engineer them to accelerate primary human prostate cell growth by releasing FGF10 as the cells secrete PSA. We expect these customizable cell culture matrices to be useful not only for culturing patient-derived prostate cancer cells, but also for a wide variety of additional cell types. This project will be a critical proof-of-concept that will establish the foundation of these materials for future development in a range of different culture contexts. The two PIs, Drs. Collier and Vander Griend, are appointed in the same department (Surgery), facilitating this collaboration aimed at solving the longstanding problem of unsuitable matrices for prostate organoid culture.