An organ-on-a-chip model system to study prostate cancer metastasis into vascularized bone

项目总结 根据“种子和土壤”理论，某些肿瘤表现出向特定器官转移的倾向。为 例如，骨骼是前列腺癌最常见的转移部位，发生在约90%的前列腺癌患者 前列腺癌晚期。芯片上器官转移模型已经成为一种强大的 癌症进展的预测指标。然而，尽管芯片上器官平台的发展，用于体外 对转移的研究，对单芯片骨转移的研究在很大程度上仍然不发达，而且只有少数 现有的模型缺乏复杂的矿化和骨细胞的包裹体，尤其是 破骨细胞进入系统，这是研究骨重建的必要元素。在这里，(目标1)我们 将使用一种新型的芯片上器官平台，具有高度矿化和钙化的细胞载水凝胶，包括 破骨细胞测定前列腺癌细胞与骨细胞矿化及相互作用的影响 前列腺癌在骨中的优先生长过程及随之而来的骨吸收一个潜在的 转移形成的限速步骤是肿瘤细胞黏附于 内皮细胞及其通过内皮细胞单层和基底膜的迁移。它有 已得到证实的是，EC毛细血管的周细胞支持是形成无渗漏血管和 因此，EC-hMSC链接的扰动会导致容器泄漏。周细胞在肿瘤转移中的作用 一直主要集中在肿瘤血管生成和这种细胞类型在癌症中的作用的研究 外渗仍然不发达。在这里，(目标2)我们将使用芯片上的骨转移平台 测试植入矿化骨基质的血管中的周细胞在抑制人前列腺中的作用 癌症渗出以及癌细胞释放的因子对血管完整性的影响。我们争辩说 这种多管齐下的策略将使体外单芯片骨转移模型系统的工程化成为可能 了解前列腺癌对骨转移的优势及对骨破坏的作用 前列腺癌中周细胞通过血管系统渗出。最终，这个项目将导致模型 可用于研究癌症到骨的转移和开发新疗法的系统。

PROJECT SUMMARY Based on “seed and soil” theory, certain tumors exhibit a predilection for metastasis to particular organs. For example, bone is the most common site of metastasis for prostate cancer, happening in ~90% of patients with advanced stages of prostate cancer. Organ-on-a-chip models of cancer metastasis have emerged as a powerful predictor of cancer progression. However, despite the development in organ-on-a-chip platforms for in-vitro studies in metastasis, research in bone metastasis on-a-chip remains largely underdeveloped, and the only few available models in the literature lack the complex mineralization and the inclusion of bone cells, especially osteoclasts into the system, which are essential elements in order to study bone remodeling. Here, (aim 1) we will use a novel organ-on-a-chip platform with a highly mineralized and calcified cell-laden hydrogel including osteoclasts to determine the influence of mineralization and the cross-talk of prostate cancer cells and bone cells on the process of preferential prostate cancer growth in bone and the consequent bone resorption. A potentially rate-limiting step in metastasis formation is the extravasation process that involves adhesion of tumor cells to endothelial cells and their transmigration through the endothelial cell monolayer and basement membrane. It has been well-established that pericyte-support of EC capillaries is required for formation of non-leaky vessels and perturbation of the EC-hMSC linkage, therefore results in leaky vessels. The role of pericytes in tumor metastasis has been mostly focused on tumor angiogenesis and the research on the role of this cell type on cancer extravasation has remained underdeveloped. Here, (aim 2) we will use the bone metastasis-on-a-chip platform to test the role of pericytes in a vasculature embedded in a mineralized bone matrix in inhibiting human prostate cancer extravasation as well as the effects of factors released by cancer cells on vasculature integrity. We argue that this multi-pronged strategy will enable the engineering of in-vitro bone metastasis-on-a-chip model system to understand the preferential metastasis of prostate cancer to the bone and bone destruction as well as the role of pericytes in prostate cancer extravasation through the vasculature. Ultimately, this project will lead to model systems that can be used for studying cancer metastasis to bone and developing new treatments.