Modeling Perineural Invasion Using a Bioorthogonally Integrated Hydrogel Platform

为了加速癌症治疗的发展，我们需要了解癌症转移，这是癌细胞从原发肿瘤部位分离并扩散到不同组织或器官的过程。除了血液和淋巴系统外，癌细胞还可以劫持神经前往远处。虽然神经引导的肿瘤传播在临床上观察到，基本机制仍然在很大程度上未知。该项目的目标是开发实验室生长的肿瘤模型，用于研究癌症-神经相互作用。前列腺癌细胞将被允许在定制设计的模具中聚集，形成紧凑的微米大小的球体。多细胞球体将嵌入凝胶状材料中，该凝胶状材料表现出刚度、降解性和细胞结合能力的空间梯度。能够释放神经细胞产生的分子的对齐的微米级合成纤维将被包括在支架中，以模拟癌症相关的神经纤维。利用这个模型，PI将研究癌细胞如何沿着神经模拟纤维生长和沿着行进。PI将确定神经引导的细胞迁移是否可以被减少癌细胞与神经关联的化合物阻断。这些研究将提高对癌症转移的认识，并加速癌症诊断和治疗的创新策略的设计，从而证明公众的支持是合理的。我们的推广和教育工作将有助于保持美国的全球竞争力。除了课程开发和学生培训，努力将致力于从事和授权的前服务，幼儿教师谁将激励下一代科学家。技术摘要：该奖项由生物材料计划在材料研究部的特拉华州大学（UD）的目的是设计一个生理相关的肿瘤模型与综合癌症神经接口，以更好地了解神经周围的入侵，在这个过程中，恶性细胞迁移沿着，周围和通过神经到远端位置。我们将通过在含有神经模拟聚合物纤维的透明质酸衍生的水凝胶基质中培养预组装的多细胞类肿瘤来实现这一目标。该工程微环境将通过一种新的界面交联方法产生，该方法采用s-四嗪和反式环辛烯衍生物之间的快速，生物正交和高效的环加成反应。水凝胶基质将表现出限定的空间梯度以促进细胞增殖、聚集和迁移，而对齐的微米级纤维将在结构上和生物化学上模拟肿瘤相关的神经纤维。我们将描述前列腺癌细胞的表型和迁移，以及它们对药理学抑制剂的反应。其目标是更好地了解恶性癌细胞的嗜神经性，加速癌症诊断和治疗的创新策略的设计。拟议的研究活动不仅将有助于下一代科学家和工程师的教育，而且还将增强幼儿教师的能力。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Non Technical Abstract:To accelerate the development of cancer therapies, we need to understand cancer metastasis, a process by which cancer cells detach from the primary tumor site and spread to a different tissue or organ. In addition to blood and lymph systems, cancer cells can hijack the nerves to travel to a distant location. Although nerve-guided tumor dissemination is clinically observed, the underlying mechanism remains largely unknown. The goal of this project is to develop lab-grown tumor models for studying cancer-nerve interactions. Prostate cancer cells will be allowed to aggregate in a custom-designed mold to form compact, micrometer-sized spheres. The multicellular spheres will be embedded in a gelatinous material exhibiting spatial gradients of stiffness, degradability and cell binding capacity. Aligned, micron-sized synthetic fibers capable of releasing molecules that nerve cells produce will be included in the scaffold to mimic the cancer-associated nerve fibers. Using this model, the PIs will investigate how cancer cells grow and travel along the nerve-mimicking fibers. The PIs will determine whether the nerve-guided cell migration can be blocked by compounds that reduce the association of cancer cells with the nerve. These studies will improve understanding of cancer metastasis and accelerate the design of innovative strategies for cancer diagnosis and treatment, thus justifying the public support. Our outreach and education efforts will help maintain the United States' global competitiveness. In addition to course development and student training, effort will be dedicated to the engaging and empowering of pre-service, early childhood teachers who will inspire the next generation scientists.Technical Abstract:This award by the Biomaterials Program in the Division of Materials Research to the University of Delaware (UD) aims to engineer a physiologically relevant tumor model with an integrated cancer-nerve interface to better understand perineural invasion, a process in which malignant cells migrate along, around and through nerves to a distal location. We will accomplish this goal by culturing pre-assembled multicellular tumoroids in a hyaluronic acid-derived hydrogel matrix containing nerve mimicking polymer fibers. The engineered microenvironment will be produced via a novel interfacial crosslinking process employing the rapid, bioorthogonal and highly efficient cycloaddition reaction between s-tetrazines and trans-cyclooctene derivatives. The hydrogel matrix will exhibit defined spatial gradients to promote cell proliferation, aggregation and migration, while the aligned, micron-sized fibers will mimic the tumor-associated nerve fibers structurally and biochemically. We will characterize the phenotype and migration of prostate cancer cells, as well as their responses to pharmacological inhibitors. The goal is to gain improved understanding of the neurotropism of malignant cancer cells, accelerating the design of innovative strategies for cancer diagnosis and treatment. The proposed research activity will not only contribute to the education of the next generation scientists and engineers, but also empower early childhood teachers. Concerted effort will be dedicated to the creation of discovery-based teaching modules, lab-based research modules and community-based design and innovation activities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.