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

癌症是美国第二大死因，每年造成50多万人死亡。尽管在治疗和早期发现方面有所改进，但转移性癌症仍然非常致命。当癌细胞扩散到身体的其他部位时，它们会与其他细胞、血管及其周围的组织环境进行通讯，这就是我们所说的肿瘤微环境(TME)。了解肿瘤细胞和其周围组织之间的这种复杂的相互作用对于找到更好的治疗和预防癌症的方法是重要的。目前，大多数癌症研究都是通过动物模型进行的。然而，动物与人类是不同的。因此，需要更好的实验模型系统来更准确地模拟人类的TME。在这个项目中，一个由生物工程和癌症生物学专家组成的团队将共同研究肿瘤细胞如何与免疫细胞、基质细胞和血管系统相互作用，并研究这些不同类型细胞之间的信号和通信，以确定阻止癌症进展的新方法。除了他们的研究目标外，该团队还旨在教育和激励下一代高中、本科生和研究生学习工程学、微流体学和癌症生物学。四重教育和外联目标包括：(A)为高中生举办暑期讲习班；(B)制作在线视频模块，向更广泛的社区广泛传播这项研究的成果；(C)组织当地专题讨论会/研讨会系列，使癌症研究人员之间产生协同作用；以及(D)促进来自代表性不足群体的学生的参与。该项目旨在利用组织工程、微流体和生物材料工具，在开发具有3D可配置层的创新的肿瘤微环境(TME)体外模型方面向前迈出重要的一步，以揭示癌细胞在侵袭和血管内侵入过程中的关键生物学指纹。研究的目标有两个：第一个目标是从机制上了解基质细胞和免疫细胞之间的生物物理信号和信号如何促进肿瘤细胞向侵袭性表型的转变；第二个目标是探索基质细胞的协调功能如何在肿瘤细胞中诱导不同的路径特征，最终导致它们进入(逃逸)血管系统。该项目代表着一项高度变革的努力，因为它汇集了各种科学学科，包括微工程、组织工程、3D成像、癌细胞生物学和功能基因组学。拟议的通用平台技术具有在多种癌症类型中应用的巨大潜力，因为它具有适应性的架构，并结合了不同的细胞和基质组件，允许在TME内进行有针对性的机制研究和个性化的治疗研究。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。

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.