Current in vivo and in vitro models of human cancer remain limited in their ability to replicate progression to invasive disease in an easily accessible and physiologically relevant format. Tissue-engineered tumors may provide a more powerful system by enabling modular control over key aspects of a tumor and its microenvironment, such as vascular density or interstitial pressure. This collaborative study seeks to develop and apply new methods of engineering vascularized tumors in vitro, in which the cellular, physical, and genetic composition of the tumor and its microenvironment can be controlled with high spatial and temporal resolution. The collaborative team consists of experts in biomaterials and tissue engineering (Tien), quantitative developmental and tumor biology (Nelson), mechanics (Ekinci), and clinical tumor biology (Radisky) and pathology (Nassar). The core enabling technology, which we have been developing over the past fifteen years, is the use of three-dimensional (3D) micropatterned extracellular matrix hydrogels as scaffolds for directing the 3D organization of engineered tissues. Specifically, the proposed work will create microscale human breast tumors that contain perfused capillaries and draining lymphatics, which provide routes for tumor cell escape and enable the capture of those cells for downstream expression profiling. Interstitial stresses and biochemical composition will be analyzed by non-invasive imaging and repeated sampling of interstitial fluid, respectively, to provide longitudinal data for correlation with tumor cell behavior. This work will also create vascularized collagenous stroma that can accept human breast tumor biopsies as in vitro patient-derived xenografts, for the discovery of candidate mutations that favor tumor invasion and escape; these mutations will then be tested in hypothesis-driven analyses using the engineered breast tumors. More broadly, this work will disseminate these microscale tissue engineering technologies to cancer research laboratories for adaptation to other types of cancers and tumor cell behaviors.
The objective of this project is to create miniature, model human tumors that enable one to study how tumors invade their surroundings and escape into neighboring vessels. The proposed work will develop new tissue engineering techniques to precisely control the spatial organization of model tumors and to subject them to defined physical and genetic changes. We intend to use these model tumors to study the signals that promote tumor cell invasion and escape, in hopes of developing rational therapies to interrupt tumor progression at these stages.
| Han, Siyang; Pang, Mei-Fong; Nelson, Celeste M (2018) Substratum stiffness tunes proliferation downstream of Wnt3a in part by regulating integrin-linked kinase and frizzled-1. J Cell Sci 131: |
| Li, Xuanyue; Xia, Jingyi; Nicolescu, Calin T et al. (2018) Engineering of microscale vascularized fat that responds to perfusion with lipoactive hormones. Biofabrication 11:014101 |
| Nerger, Bryan A; Nelson, Celeste M (2018) 3D culture models for studying branching morphogenesis in the mammary gland and mammalian lung. Biomaterials : |
| Thompson, Rebecca L; Margolis, Emily A; Ryan, Tyler J et al. (2018) Design principles for lymphatic drainage of fluid and solutes from collagen scaffolds. J Biomed Mater Res A 106:106-114 |
| Kourouklis, Andreas P; Nelson, Celeste M (2018) Modeling branching morphogenesis using materials with programmable mechanical instabilities. Curr Opin Biomed Eng 6:66-73 |
