Image-based Systems Biology of Vascular Co-option in Brain Tumors

摘要： 最近的临床和临床前证据表明，胶质瘤最初可以生长、侵袭、逃避抗血管生成治疗。 并最终通过劫持或“拉拢”大脑先前存在的血管而复发。血管增选是一种 非血管生成胶质瘤的生长机制，其中，增选肿瘤细胞导致星形胶质细胞失去与 血管，即引起胶质血管解偶联(GVU)，并改变脑血流动力学。此外，在激进的高- 恶性胶质瘤(如胶质母细胞瘤或GBM)，血管选择性促进癌细胞迁移和侵袭 健康的脑组织。然而，血管选择性的演变对胶质瘤的生存期、结果GVU和血流动力学的影响 由于缺乏微血管分辨率生命周期和多模式/多尺度，变化仍然知之甚少 成像方法。此外，由于缺乏对比剂，结缔组织胶质瘤的生长在放射学上是无法检测到的。 常规MRI(如T2/FLAIR)方法的增强和缺乏特异性。因此，我们的目标是使用 基于图像的系统生物学方法阐明增生性胶质瘤的生命周期和血流动力学 建立共选诱导GVU的fMRI生物标志物。在令人信服的初步数据的指导下，我们将追求三个 具体目标：(1)表征患者来源的异种胶质瘤(PDX)在其生命周期中的血管选择性 多尺度成像；(2)建立基于图像的血管选择性脑血流动力学变化模型 在胶质瘤中；以及(3)确定rS-fMRI是否可以在患者来源的胶质瘤异种移植中检测到血管共选诱导的GVU。 在Aim1下，我们提出了一种范式转换方法，该方法使用微型显微镜来实现微血管分辨率(~5微米) 共选择性诱导的脑胶质瘤患者生命周期内血流动力学变化的多对比体内成像 异种移植。我们将用多模式/多尺度的全脑数据来补充这些微血管尺度的测量 从同一动物的体外CT/MRI/光片显微镜(LSM)到相关的结构/功能/细胞变化 在血管微环境(VME)。在AIM2下，我们将这些数据用于共同选择诱导模型 血流动力学失调模拟全脑变化，可作为COP的fMRI生物标记物 神经胶质瘤。在Aim3下，我们将确定静息状态fmri(rs-fmri)是否可以检测到选择性PDX中的GVU并区分 它源于非结缔组织胶质瘤的生长。我们的方法是创新的，因为它融合了尖端的进步和微型化 显微镜、多尺度/多模式成像和基于图像的系统生物学。这项拟议的研究具有重要意义 因为这些研究将建立：(I)可免费下载、共同登记的癌症系统生物学多尺度数据 研究人员；(Ii)共选择性胶质瘤的血流动力学模型；(Iii)一种新的胶质瘤选择性生物标记物 改变患者管理，刺激治疗方法的发展，以阻止抗血管生成耐药。我们 也希望这种方法适用于其他依赖血管选择性的中枢神经系统疾病(例如脑转移瘤)。

ABSTRACT: Recent clinical and preclinical evidence has shown that gliomas can initially grow, invade, evade antiangiogenic therapies and eventually recur by hijacking or “co-opting” the brain’s preexisting blood vessels. Vascular co-option is a nonangiogenic glioma growth mechanism in which, co-opting tumor cells cause astrocytes to lose intimate contact with blood vessels, i.e. cause gliovascular uncoupling (GVU), and alter cerebral hemodynamics. Additionally, in aggressive high- grade gliomas (e.g. glioblastoma or GBM), vessel co-option facilitates the migration and invasion of cancer cells into healthy brain tissue. Yet, the evolution of vessel co-option over the glioma’s life-time, resultant GVU and hemodynamic changes remain poorly understood due to a lack of microvascular-resolution lifecycle and multimodality/multiscale imaging approaches. Moreover, co-optive glioma growth is radiologically undetectable due to an absence of contrast enhancement and the lack of specificity of conventional MRI (e.g. T2/FLAIR) approaches. Therefore, our goal is to use an image-based systems biology approach to elucidate the hemodynamics of co-optive glioma over its lifecycle and develop an fMRI biomarker of co-option induced GVU. Guided by compelling preliminary data, we will pursue three Specific Aims: (1) Characterize vessel co-option in a patient-derived glioma xenograft (PDX) over its lifecycle with multiscale imaging; (2) Develop an image-based model of brain-wide hemodynamic changes induced by vessel co-option in glioma; and (3) Determine if rs-fMRI can detect vessel co-option induced GVU in a patient-derived glioma xenograft. Under Aim1, we propose a paradigm-shifting approach that employs a miniscope for microvessel resolution (~5 µm) multicontrast in vivo imaging of co-option induced hemodynamic changes over the lifecycle of a patient-derived glioma xenograft. We will complement these microvascular-scale measurements with multimodality/multiscale whole-brain data from ex vivo CT/MRI/light sheet microscopy (LSM) in the same animal to corelate structural/functional/cellular changes in the vascular microenvironment (VME). Under Aim2, we employ these data in a model of co-option induced hemodynamic dysregulation to simulate brain-wide changes that could be exploited as fMRI biomarkers of co-optive glioma. Under Aim3, we will determine if resting-state fMRI (rs-fMRI) can detect GVU in a co-optive PDX and differentiate it from non-co-optive glioma growth. Our approach is innovative because it blends cutting-edge advances in miniaturized microscopy, multiscale/multimodality imaging and image-based systems biology. The proposed research is significant because these studies will establish: (i) freely downloadable, co-registered multiscale data for cancer systems biology investigators; (ii) a hemodynamic model for co-optive glioma; (iii) a novel biomarker of glioma co-option with the potential to transform patient management and stimulate the development of therapies to thwart antiangiogenic resistance. We also expect this approach to be adaptable to other CNS diseases dependent on vessel co-option (e.g. brain metastases).