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这种毁灭性疾病的所有当前治疗方法。因此，阻止这一过程可能会将胶质瘤从侵袭性的全脑疾病转变为局部疾病--这种疾病可以用目前的局部治疗方法有效地治疗，如手术或准直放射治疗。因此，迫切需要开发有效的抗侵入性治疗方法。然而，要做到这一点，需要详细了解胶质瘤的运动和侵袭机制。为了解决这个问题，Odde博士和Rosenfeld博士最近发起了一项合作，为胶质瘤运动性的机械力化学基础开发计算模型，并为大脑微观力学和微结构建立体外模型。我们有令人信服的初步结果，如下所述，这些结果表明，在高硬度的底物上，胶质瘤细胞的运动方式与我们在体内脑侵袭中描述的非常相似，而在低硬度的底物上，它们明显分化。我们现在建议扩大这些研究，以了解胶质瘤运动的基本机制，以最终控制脑癌患者胶质瘤扩散的过程。我们的初步研究将旨在应对以下挑战：1)开发作为环境机械硬度和微结构的函数的胶质瘤迁移的预测计算模型2)开发体外微系统以模拟体内的微结构和机械特性3)测量迁移的胶质瘤所感知的大脑微机械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和类体内微系统的工程(ODDE)到体内运动性和动物研究(Rosenfeld)。此外，由于罗森菲尔德博士还领导着东北部最大的脑瘤临床研究中心之一，我们处于有利地位，最终将把我们的发现转化为早期临床试验。我们认为，最近发起的这项合作是独一无二的，它将建模、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。通过解决这些挑战，我们将能够开发出预测胶质瘤在啮齿动物脑片中迁移的模型，并最终在完整的人脑中迁移。我们的目标将是使用这些胶质瘤迁移的机械力化学模型来指导新的治疗策略的开发，以干扰胶质瘤在脑内的扩散。 公共卫生相关性：脑癌是一种毁灭性的疾病，其原因是癌细胞在大脑中逐渐扩散。我们将从根本上开发新的工具来了解脑癌细胞运动的力学基础，然后这些工具将指导新的治疗策略。

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.