Microengineering of Organotypic and Vascularized Tumor Microenvironment Models for Mechanistic Studies of the Metastatic Cascade

Cancer is the second leading cause of death in the United States, causing over half a million deaths each year. Although there have been improvements in treatment and early detection, metastatic cancers remain very deadly. When cancer cells spread to other parts of the body, they communicate with other cells, blood vessels, and their surrounding tissue environment, known as the "tumor microenvironment (TME)". Understanding this complex interaction between tumor cells and their surroundings tissue is important for finding better ways to treat and prevent cancer. Currently, most cancer research is performed using animal models. However, animals are different from humans. Therefore, there is a need for better experimental model systems that can mimic the human TME more accurately. In this project, a team of experts in bioengineering and cancer biology will work together to study how tumor cells interact with immune cells, stromal cells, and the vascular system and to investigate the signals and communication between these different cell types to identify new ways to block the progression of cancer. In addition to their research goals, the team also aims to educate and inspire the next generation of students in high school, undergraduate, and graduate programs to learn about engineering, microfluidics, and cancer biology. The four-fold educational and outreach objectives include: (A) Developing a summer workshop for high school students; (B) Creating online video modules to broadly disseminate the outcome of this study to the broader community; (C) Organizing local symposium/seminar series to bring synergy among cancer researchers; and (D) Promoting the involvement of students from underrepresented groups. This project aims to take a significant step forward in developing innovative ex vivo models of the tumor microenvironment (TME) with 3D configurable layers, utilizing tissue engineering, microfluidics, and biomaterials tools, to uncover critical biological insights into the cellular and molecular fingerprints of cancer cells during invasion and intravasation. The research objectives are two-fold: the first Objective is to mechanistically understand how the biophysical cues and signaling between stromal and immune cells contribute to the transition of tumor cells into an invasive phenotype and the second Objective is to explore how the coordinated function of stromal cells induces distinct pathway signatures in tumor cells, ultimately leading to their intravasation (escape) into the vascular system. This project represents a highly transformative endeavor, as it brings together various scientific disciplines, including microengineering, tissue engineering, 3D imaging, cancer cell biology, and functional genomics. The proposed universal platform technology holds great potential for application across multiple cancer types, due to its adaptable architecture and incorporation of diverse cellular and matrix components, allowing for targeted mechanistic studies and personalized therapeutic investigations within the TME. 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.