Multiscale hydrogel biomaterials-enabled 3D modeling of cancer drug resistance

点击翻译按钮获取中文摘要

Project Summary/Abstract Developing new anticancer drugs has been very slow and costly. A major reason is that the commonly used 2D cancer cells and animal models for drug discovery today are very different from the 3D tumors in human patients. Lately, 3D tumor models have been made by suspending tumor cells in medium to form multicellular spheroids/organoids, growing the cells in hydrogels/scaffolds, and incorporating blood vessels. However, little has been done to build 3D vascularized tumor models for recapitulating the drug resistance in patient tumors. We recently developed a novel multiscale hydrogel biomaterials-based bottom-up strategy to control the formation of the two distinct tissue domains in tumors - a 3D vascular network and an avascular/intervascular tumor cell-containing region, for studying cancer drug resistance. This is achieved by producing 3D avascular micro-tumors (µtumors) first and using them as the building blocks for assembling with endothelial cells (ECs) under dynamic perfusion culture, to form 3D vascularized tumors with a complex 3D vascular network that mimics the vascular-intervascular organization of in vivo tumors. Importantly, our data show quantitatively for the first time that, the 3D vascularized tumors are much more drug resistant than 3D avascular µtumors, indicating tumor blood vessels not only transport nutrients/oxygen but also enhance cancer drug resistance. However, no 3D vascularized tumor was built in vitro with cells differentiated from cancer stem cells (CSCs) for drug discovery, although the rare CSCs have been posited to possess the exclusive ability of tumorigenesis and be responsible for the many failures of cancer chemotherapy due to their high drug resistance. Moreover, no CSCs isolated with contemporary methods are shown to differentiate into a type of cells that are not in tumors. This cross-tissue multilineage differentiation is a key property of stem cells (e.g., adipose-derived stem cells can differentiate into osteoblasts that are absent in fat). Thus, a method for isolating true CSCs is in need. We recently developed a novel core-shell hydrogel biomaterials-based approach for isolating CSCs by culturing one (1) single cancer cell (from a cell line) in the nanoliter hydrogel core of microcapsules that mimic pre-hatching embryos, where totipotent-pluripotent stem cells are cultured in human body. Importantly, the isolated CSCs are capable of endothelial, cardiac, neural, and osteogenic differentiations and highly tumorigenic, metastatic, and drug resistant, indicating the cells isolated with our bioinspired 1-cell culture are truly CSCs. In this project, we propose to further develop the novel bioinspired approach for isolating CSCs from breast tumors of human patients. In view of the highly drug resistant nature of the CSCs isolated with our bioinspired 1-cell culture and their ability of differentiating into ECs in vivo that may reduce patient survival, we further propose to use the CSC-derived ECs and cancer cells for building 3D vascularized tumors, to better model the drug resistance in patient tumors than existing 3D vascularized tumors made using non-CSC cancer cells and non-CSC (and often non-cancer-related) ECs (e.g., human umbilical vein endothelial cells known as HUVECs).