Modeling Perineural Invasion Using a Bioorthogonally Integrated Hydrogel Platform

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，将其转移到远处。虽然临床观察到神经引导的肿瘤播散，但其潜在机制仍不清楚。该项目的目标是开发实验室培养的肿瘤模型，用于研究癌症与神经的相互作用。前列腺癌细胞将被允许聚集在一个定制设计的模具中，形成紧凑的微米大小的球体。多细胞球体将被嵌入一种凝胶状材料中，这种材料表现出刚度、可降解性和细胞结合能力的空间梯度。排列整齐，微米大小的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。利用这个模型，pi将研究癌细胞是如何沿着神经模拟纤维生长和移动的。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阻断。这些研究将提高对癌症转移的认识，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。我们的外联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之外，我们还将致力于培养能够激励下一代科学家的学前幼儿教师。技术摘要：该奖项由特拉华大学（UD）材料研究部生物材料项目颁发，旨在设计一种具有综合癌症-神经界面的生理相关肿瘤模型，以更好地理解神经周侵袭，即恶性细胞沿神经、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。工程微环境将通过一种新的界面交联工艺产生，该工艺采用s-四嗪和反式环烯衍生物之间的快速、生物正交和高效环加成反应。水凝胶基质将表现出明确的空间梯度，以促进细胞增殖、聚集和迁移，而排列的微米级纤维将在结构和生化上模仿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，以及它们对药物抑制剂的反应。目标是提高对恶性癌细胞嗜神经性的理解，加速设计癌症诊断和治疗的创新策略。拟议的研究活动不仅有助于下一代科学家和工程师的教育，而且还将赋予幼儿教师权力。我们将共同努力创建以发现为基础的教学模块、以实验室为基础的研究模块以及以社区为基础的设计和创新活动。该奖项反映了美国国家科学基金会的法定使命，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.