Modeling Perineural Invasion Using a Bioorthogonally Integrated Hydrogel Platform

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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.