Modeling Perineural Invasion Using a Bioorthogonally Integrated Hydrogel Platform

非技术摘要：为了加速癌症治疗的发展，我们需要了解癌症转移，即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，癌细胞还可以劫持神经，使其传播到遥远的地方。虽然临床上观察到神经引导的肿瘤扩散，但其潜在的机制仍然很大程度上是未知的。该项目的目标是开发实验室生长的肿瘤模型，用于研究癌症与神经的相互作用。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。多细胞球体将被嵌入到一种胶状材料中，显示出刚性、降解性和细胞结合能力的空间梯度。排列整齐的微米级合成纤维能够释放神经细胞产生的分子，将被包括在支架中，以模拟与癌症相关的神经纤维。利用这一模型，PI将研究癌细胞是如何沿着模仿神经的纤维生长和移动的。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联系的化合物所阻断。这些研究将提高对癌症转移的了解，并加快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。我们的外展和教育努力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，还将致力于吸引和增强职前幼儿教师的能力，他们将激励下一代科学家。技术摘要：该奖项由特拉华大学材料研究部生物材料计划授予特拉华大学(UD)，旨在设计一种具有整合的癌症-神经界面的生理相关肿瘤模型，以更好地了解神经周侵袭，这是一个恶性细胞沿着、周围和通过神经迁移到远端位置的过程。我们将通过在含有神经模拟聚合物纤维的透明质酸衍生水凝胶基质中培养预先组装的多细胞类肿瘤来实现这一目标。工程微环境将通过一种新的界面交联过程来实现，该过程采用S-四氮杂环与反式环辛烯衍生物之间快速、生物正交和高效的环加成反应。水凝胶基质将显示出特定的空间梯度，以促进细胞的增殖、聚集和迁移，而排列的微米级纤维将在结构和生化上模拟肿瘤相关神经纤维。我们将描述前列腺癌细胞的表型和迁移，以及它们对药物抑制剂的反应。其目标是更好地了解恶性癌细胞的神经趋向性，加快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，还将赋予幼儿教师权力。该奖项将致力于创建基于发现的教学模块、基于实验室的研究模块以及基于社区的设计和创新活动。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.