Predicting How Fluid-Solid Transitions in Cancer Tumors Help Govern Invasion and Metastasis

在癌症的临床治疗中出现的两个重要问题是1）识别肿瘤边界以指导手术切除和2）识别准确预测个体患者中癌症的侵袭性/侵袭性的生物标志物。本提案中的工作将使用与目前癌症生物学中正在探索的不同但互补的想法来解决这两个问题。具体来说，PI将识别肿瘤的机械状态，并使用该信息来量化负责组织凝聚力和边界维持的机制。这将使他们能够开发结构有序参数，如细胞形状，组织硬度或粘附分子表达，更好地描绘组织边界，供病理学家或临床医生将来使用。PI还将测试这样的猜想，即结合其理论框架，组织融合实验的测量或来自原发性肿瘤样本的细胞硬度分布可以作为癌症侵袭性的非常准确的机械生物标志物。此外，拟议的工作将扩大对生物物理学跨学科领域的参与，因为研究所将培训一批多样化的本科生、研究生和博士后，并组织会议和学校，为大量年轻科学家提供专业发展机会。虽然一种称为基底膜的物理屏障最初包裹着许多原发性肿瘤，但即使细胞突破该屏障，肿瘤边界也通常保持不变。维持和调节这些边界的机械和生物化学机制知之甚少。PI最近一起开发并实验验证了一个理论框架，该框架首次解释了融合组织中的流体到固体的转变，其中细胞之间没有间隙。越来越多的证据表明，这种转变也发生在癌组织中。由于类流体和类固体组织具有不同的迁移，自组织和凝聚机制，该提案将增强和测试癌症组织堵塞的理论框架，并研究流体到固体的转变如何影响肿瘤边界。特别是，PI将扩展他们的框架，对癌症组织边界如何在不同的实验几何形状中演变进行可测试的定量预测，并开发新的理论技术，用于预测机械异质性如何导致刚性渗透和自组织软细胞的流状流动。第二项新技术将组织模型与细胞外基质模型相结合，以了解逃逸细胞的机械特性和运动模式如何受到原发性肿瘤和周围基质的机械特性的影响。

Two important issues that arise in clinical treatment of carcinomas are 1) identification of tumor boundaries to guide surgical resection and 2) identification of biomarkers that accurately predict the invasiveness/aggressiveness of carcinomas in individual patients. The work in this proposal will address both of these issues using ideas that are different from yet complementary to ones currently being explored in cancer biology. Specifically, the PIs will identify the mechanical state of the tumor and use that information to quantify the mechanisms that are responsible for tissue cohesion and boundary maintenance. This will allow them to develop structural order parameters such as cell shape, tissue stiffness, or adhesion molecule expression that better delineate tissue boundaries for future use by pathologists or clinicians. The PIs will also test the conjecture that in combination with their theoretical framework, measurements of tissue fusion experiments or distributions of cell stiffness from primary tumor samples can serve as very accurate mechanical biomarkers for cancer aggressiveness. In addition, the proposed work will broaden participation in the interdisciplinary field of biophysics as the PIs will train a diverse group of undergraduate and graduate students and postdocs, as well as organize conferences and schools that provide professional development opportunities for a large number of young scientists. Although a physical barrier called the basement membrane initially encapsulates many primary tumors, tumor boundaries are often maintained even when cells break through that barrier. The mechanical and biochemical mechanisms that maintain and regulate these boundaries are poorly understood. Together, the PIs have very recently developed and experimentally verified a theoretical framework that for the first time explains fluid-to-solid transitions in confluent tissues, where there are no gaps between cells. There is mounting evidence that such transitions also occur in cancer tissues. Because fluid-like and solid-like tissues have different mechanisms for migration, self-organization, and cohesion, this proposal will augment and test a theoretical framework for jamming for cancer tissues and investigate how fluid-to-solid transitions affect tumor boundaries. In particular, the PIs will extend their framework to make testable, quantitative predictions for how cancer tissue boundaries evolve in different experimental geometries, and develop new theoretical techniques for predicting how mechanical heterogeneity can lead to rigidity percolation and self-organization of stream-like flows of soft cells. A second new technique will couple tissue models to extra-cellular matrix models to understand how the mechanical properties and motility modes of escaping cells are influenced by the mechanical properties of both the primary tumor and surrounding substrate.