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

基于多尺度水凝胶生物材料的癌症耐药性 3D 建模

基本信息

批准号：
10639167
负责人：
Xiaoming He
金额：
$ 44.03万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10639167
关键词：
3-Dimensional Acceleration American Animal Cancer Model Animal Model Antineoplastic Agents Biocompatible Materials Blood Vessels Bone Marrow Bone Marrow Stem Cell Breast Cancer Cell Breast Cancer Patient Cancer Etiology Cancer Patient Cardiac Cause of Death Cell Culture Techniques Cell Line Cell Separation Cell Survival Cell model Cells Cellular Spheroids Cessation of life Chemotherapy-Oncologic Procedure Chondrocytes Collagen Collecting Cell Complex Data Devices Drug Modelings Drug resistance Embryo Encapsulated Endothelial Cells Endothelium Engineering Epidermal Growth Factor Receptor Failure Fatty acid glycerol esters Foundations Frequencies Gene Expression Histology Home Human Human body Hydrogels In Vitro Individual Label MDA MB 231 Malignant Neoplasms Mammary Neoplasms Methods Microcapsules drug delivery system Microfluidics Modeling Mus Nature Neoplasm Metastasis Neoplasms in Vascular Tissue Nutrient Organoids Osteoblasts Oxygen Patients Perfusion Permeability Play Pluripotent Stem Cells Proliferating Property Prostatic Neoplasms Public Health Recurrent Malignant Neoplasm Reporting Role Stromal Cells Study models Surface Suspension Culture Technology Testing Time Tissues Totipotent Tumor Stem Cells Umbilical vein Vascularization Woman adipose derived stem cell cancer cell cancer cell differentiation cancer drug resistance cancer recurrence cancer stem cell cancer subtypes carcinogenesis cell motility cell type combat cost drug discovery endothelial stem cell engineered stem cells hatching human stem cells in vivo innovation malignant breast neoplasm mortality nanolitre neoplastic cell neural novel novel anticancer drug osteogenic ovarian neoplasm protein expression rare cancer scaffold stem cells targeted treatment three dimensional cell culture three-dimensional modeling triple-negative invasive breast carcinoma tumor tumorigenesis tumorigenic

3-Dimensional Acceleration American Animal Cancer Model Animal Model Antineoplastic Agents Biocompatible Materials Blood Vessels Bone Marrow Bone Marrow Stem Cell Breast Cancer Cell Breast Cancer Patient Cancer Etiology Cancer Patient Cardiac Cause of Death Cell Culture Techniques Cell Line Cell Separation Cell Survival Cell model Cells Cellular Spheroids Cessation of life Chemotherapy-Oncologic Procedure Chondrocytes Collagen Collecting Cell Complex Data Devices Drug Modelings Drug resistance Embryo Encapsulated Endothelial Cells Endothelium Engineering Epidermal Growth Factor Receptor Failure Fatty acid glycerol esters Foundations Frequencies Gene Expression Histology Home Human Human body Hydrogels In Vitro Individual Label MDA MB 231 Malignant Neoplasms Mammary Neoplasms Methods Microcapsules drug delivery system Microfluidics Modeling Mus Nature Neoplasm Metastasis Neoplasms in Vascular Tissue Nutrient Organoids Osteoblasts Oxygen Patients Perfusion Permeability Play Pluripotent Stem Cells Proliferating Property Prostatic Neoplasms Public Health Recurrent Malignant Neoplasm Reporting Role Stromal Cells Study models Surface Suspension Culture Technology Testing Time Tissues Totipotent Tumor Stem Cells Umbilical vein Vascularization Woman adipose derived stem cell cancer cell cancer cell differentiation cancer drug resistance cancer recurrence cancer stem cell cancer subtypes carcinogenesis cell motility cell type combat cost drug discovery endothelial stem cell engineered stem cells hatching human stem cells in vivo innovation malignant breast neoplasm mortality nanolitre neoplastic cell neural novel novel anticancer drug osteogenic ovarian neoplasm protein expression rare cancer scaffold stem cells targeted treatment three dimensional cell culture three-dimensional modeling triple-negative invasive breast carcinoma tumor tumorigenesis tumorigenic

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项目摘要

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).

项目摘要/摘要开发新的抗癌药物非常缓慢且昂贵。主要原因是常用当今的2D癌细胞和动物模型与人类的3D肿瘤大不相同患者。最近，已经通过将肿瘤细胞悬浮在培养基中形成多细胞而制作了3D肿瘤模型球体/器官，在水凝胶/支架中生长细胞，并增加血管。但是，很少已经进行了建立3D血管化肿瘤模型，以概括患者肿瘤中的耐药性。我们最近开发了一种新型的多尺度水凝胶生物材料的自下而上策略，以控制肿瘤中两个不同的组织结构域的形成 - 一个3D血管网络和无血管/静止含肿瘤细胞的区域，用于研究癌症耐药性。这是通过产生3D血管来实现的首先，微肿瘤（µTumors），并将它们用作组装内皮细胞（EC）的构件在动态灌注培养物下，与复杂的3D血管网络形成3D血管化肿瘤模仿体内肿瘤的血管间血管组织。重要的是，我们的数据定量显示 3D血管化肿瘤第一次比3D血管µTumors更具药物抗药性，表明肿瘤血管不仅输送养分/氧气，还可以增强癌症耐药性。然而，在体外没有3D血管化肿瘤，与癌细胞分化的细胞（CSC）建立对于药物发现，尽管稀有的CSC已被分配为具有肿瘤发生的独家能力并因其耐药性高而负责癌症化学疗法的许多失败。而且，没有证明使用现代方法隔离的CSC可以分化为不在肿瘤。这种跨组织多曲线分化是干细胞的关键特性（例如，脂肪衍生的茎细胞可以区分脂肪中不存在的成骨细胞。这是需要一种隔离真正CSC的方法。我们最近开发了一种新型的核壳水凝胶生物材料方法，用于通过培养一个（1）单个癌细胞（来自细胞系），在微胶囊的纳米素水凝胶核心中预录胚，其中整整素的干细胞在人体中培养。重要的是，孤立的CSC能够内皮，心脏，神经和成骨分化和高度肿瘤性，转移性和耐药性，表明用我们的生物启发的1细胞培养分离的细胞是真正的CSC。在这个项目中，我们建议进一步开发新型的生物启发方法，以使CSC与乳房隔离人类患者的肿瘤。鉴于与我们的生物启发的CSC的高度耐药性 1细胞培养及其在体内区分EC的能力，从而可以降低患者的生存，我们进一步建议使用CSC衍生的EC和癌细胞来构建3D血管化肿瘤，以更好地建模患者肿瘤中的耐药性比使用非CSC癌细胞制成的现有3D血管化肿瘤和非CSC（通常是非癌症相关的）EC（例如，被称为HUVEC的人脐静脉内皮细胞）。