Microsystems and modeling approach to glioma migration and metastasis

描述（由申请人提供）：本申请涉及广泛的挑战领域（06）使能技术和特定的挑战主题，06- CA-116：物理科学和细胞力学恶性胶质瘤细胞侵入正常大脑的能力严重限制了目前对这种毁灭性疾病的所有治疗方法。因此，阻断这一过程可以将神经胶质瘤从侵袭性全脑疾病转变为局部疾病——可以用目前的局部治疗方法有效治疗，如手术或准直放射治疗。因此，迫切需要开发有效的抗侵入治疗方法。然而，这样做需要对胶质瘤运动和侵袭的机制有详细的了解。为了解决这个问题，dr。Odde和Rosenfeld最近开始合作开发神经胶质瘤运动的机械化学基础的计算模型，以及大脑微力学和微结构的体外模型。我们有令人信服的初步结果，如下所述，这表明在高硬度的底物上，胶质瘤细胞以一种与我们在体内脑入侵中描述的非常相似的方式移动，而在低硬度的底物上，它们明显分化。我们现在建议扩展这些研究，以了解胶质瘤运动的基本机制，最终控制胶质瘤在脑癌患者中的扩散过程。我们的初步研究旨在应付以下挑战：1)开发胶质瘤迁移的预测计算模型，作为环境机械刚度和微结构的函数2)开发体外微系统来模拟体内微结构和机械特性3)测量迁移胶质瘤所感知的大脑微力学特性我们相信，我们的合作将产生很大的影响，因为它跨越了广泛的科学主题——从细胞力学的基本建模到体内样结构的工程微系统（Odde）到体内运动和动物研究（Rosenfeld）。此外，由于Rosenfeld博士还指导东北地区最大的脑肿瘤临床研究中心之一，我们很好地定位于最终将我们的发现转化为早期临床试验。我们相信这个最近发起的合作，将建模、微系统、细胞生物学、恶性胶质瘤的动物模型开发和临床神经肿瘤学结合在一起，是独一无二的。通过解决这些挑战，我们将能够在啮齿动物大脑切片中开发胶质瘤迁移的预测模型，并最终在完整的人类大脑中开发。我们的目标是利用这些神经胶质瘤迁移的机械化学模型来指导新的治疗策略的发展，以干扰脑内神经胶质瘤的分散。

DESCRIPTION (provided by applicant): This application address broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06- CA-116: Physical Sciences and Cellular Mechanics The ability of malignant glioma cells to invade normal brain severely limits all current therapies for this devastating disease. Blocking this process could therefore convert gliomas from an invasive, whole brain disease to a local disease-one that could be effectively treated with current local therapies, such as surgery or collimated radiation therapy. Thus, there is a pressing need to develop effective anti-invasive treatments. However, doing so will require a detailed understanding of the mechanics of glioma movement and invasion. To address this issue, Drs. Odde and Rosenfeld recently initiated a collaboration to develop computational models for the mechanochemical basis of glioma motility and in vitro models for brain micromechanics and microarchitecture. We have compelling preliminary results, described below, which show that on substrates of high stiffness, glioma cells move in a manner very similar to what we have described in in vivo brain invasion, while on substrates of low stiffness, they diverge significantly. We now propose to extend these studies to understand the fundamental mechanics of glioma motility to ultimately control the process of glioma dispersion in brain cancer patients. Our initial studies will aim to meet the following challenges: 1) Develop predictive computational models for glioma migration as a function of environmental mechanical stiffness and micro-architecture 2) Develop in vitro microsystems to mimic in vivo micro-architecture and mechanical properties 3) Measure the brain micromechanical properties that are sensed by migrating gliomas We believe that our collaboration will have a high impact because it spans a broad range of scientific themes-- from basic modeling of cell mechanics and engineering of in vivo-like microsystems (Odde) to in vivo motility and animal studies (Rosenfeld). Furthermore, since Dr. Rosenfeld also directs one of the largest brain tumor clinical research centers in the Northeast, we are well positioned to ultimately translate our findings into early stage clinical trials. We believe that this recently initiated collaboration, which brings together modeling, microsystems, cell biology, animal model development of malignant gliomas, and clinical neuro-oncology, is unique. By addressing these challenges, we will be in position to develop predictive models for glioma migration in rodent brain slices, and ultimately in intact human brains. Our goal will be to use these mechanochemical models for glioma migration to guide development of novel therapeutic strategies to interfere with glioma dispersion within the brain. PUBLIC HEALTH RELEVANCE: Brain cancer is a devastating disease due to the progressive spreading of cancer cells throughout the brain. We will develop fundamentally new tools for understanding the mechanical basis of brain cancer cell movement, which will then guide novel therapeutic strategies.