BRAVE hydrogels for interrogating cell-matrix interactions in pancreatic desmoplasia

BRAVE 水凝胶用于研究胰腺结缔组织增生中的细胞-基质相互作用

基本信息

批准号：
10524112
负责人：
Chien-Chi Lin
金额：
$ 6.92万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-20 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524112
关键词：
3-Dimensional Address Applied Research Automobile Driving Basic Science Biochemical Biomimetics Biophysics Cancer Patient Cell Communication Cells Cellular Assay Cessation of life Chemoresistance Clinical Coculture Techniques Collagen Communication Cues Desmoplastic Devices Disease Drug Targeting Encapsulated Engineering Environment Enzymes Epithelial Extracellular Matrix Fibroblasts Fibronectins Gel Gelatin Goals Hyaluronic Acid Hybrids Hydrogels Immunooncology In Situ In Vitro Malignant Neoplasms Malignant neoplasm of pancreas Mechanics Mesenchymal Molecular Molecular Target Neoplasm Metastasis Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pathologic Play Polymers Process Property Reporting Research Role Solid Neoplasm Stromal Cells Stromal Neoplasm Survival Rate System Technology Therapeutic Tissues Treatment outcome Visible Radiation Work anti-cancer therapeutic cancer cell cell behavior cell motility cell stroma cytokine design drug discovery effective therapy efficacy testing improved inhibitor insight migration mimetics novel pancreatic cancer cells pancreatic desmoplasia pancreatic ductal adenocarcinoma cell prevent screening stem cell differentiation success synergism tissue regeneration tumor tumor microenvironment tumor progression viscoelasticity

项目摘要

PROJECT SUMMARY/ABSTRACT With a dismal 5-year survival rate of ~8%, pancreatic cancer is projected to become the second leading cause of all cancer-related deaths by 2030. While many therapeutics against pancreatic cancer have been identified, treatment of this disease remains challenging owing to the exceptionally dense and hypovascularized stromal tissue. Therefore, deeper understanding of tumor-stroma interactions in a viscoelastic matrix will facilitate the identification of novel molecular targets against this deadly disease. Polymeric hydrogels capable of recapitulating aspects of the extracellular matrix (ECM) are ideal for studying cancer cell fate as these gels can be engineered with precise biophysical and/or biochemical properties that emulate the tumor ECM. The long- term objective of this project is to use bio-inspired, responsive, and viscoelastic (BRAVE) matrices for elucidating molecular mechanisms governing progression of pancreatic cancer cells (PCCs), as well as for identifying novel molecular targets to improve treatment outcome. In this R01 project, we will develop BRAVE hydrogels composed of functionalized hyaluronic acid and gelatin, as well as collagen and fibronectin for interrogating matrix factors guiding pancreatic cell behaviors. In Aim 1, we will develop the said BRAVE hydrogels to define the synergisms between major matrix components (e.g., HA, FN, and matrix viscoelasticity) on PCC progression. In Aim 2, we will prepare BRAVE hydrogels compatible with high-content assay (HCA) of cell fate processes. We will also design dual-layer BRAVE gels with identical biochemical compositions but spatially graded mechanics for co-culturing PCCs and patient-derived cancer associated fibroblasts (PD-CAFs), the major tumor stromal cells. This platform will provide direct experimental evidence regarding the necessity of a stiffened matrix on cell-cell crosstalk and EMT in PCCs. In Aim 3, we will develop BRAVE gel with gradient stiffness to interrogate PCC migration (i.e., durotaxis) under the influence of various matrix factors (e.g., cytokines, CAFs, and inhibitors). The results will provide insights regarding PCC migration/invasion and potential molecular targets against PCC metastasis. The BRAVE hydrogels and durotaxis device developed in this proposal will allow us to answer many pancreatic cancer relevant questions that are otherwise difficult to address. Furthermore, the outcome of this project will have impact on basic and applied research in other cancers, as well as on directed stem cell differentiation for tissue regeneration.

项目概要/摘要胰腺癌的 5 年生存率约为 8%，预计将成为第二大病因到 2030 年，所有癌症相关死亡人数将占所有癌症相关死亡的比例。虽然已经找到了许多针对胰腺癌的治疗方法，由于基质异常致密且血管化不足，这种疾病的治疗仍然具有挑战性组织。因此，更深入地了解粘弹性基质中的肿瘤-基质相互作用将有助于识别针对这种致命疾病的新分子靶标。聚合水凝胶能够概括细胞外基质 (ECM) 的各个方面，是研究癌细胞命运的理想选择，因为这些凝胶可以被设计为具有模拟肿瘤 ECM 的精确生物物理和/或生化特性。长- 该项目的长期目标是使用仿生、响应和粘弹性（BRAVE）矩阵来阐明控制胰腺癌细胞（PCC）进展的分子机制，以及识别新的改善治疗效果的分子靶标。在这个R01项目中，我们将开发BRAVE水凝胶由功能化透明质酸和明胶以及胶原蛋白和纤连蛋白组成，用于研究指导胰腺细胞行为的基质因素。在目标 1 中，我们将开发上述 BRAVE 水凝胶来定义主要基质成分（例如 HA、FN 和基质粘弹性）之间对 PCC 进展的协同作用。在目标 2 中，我们将制备与细胞命运过程的高内涵测定 (HCA) 兼容的 BRAVE 水凝胶。我们还将设计具有相同生化成分但空间分级的双层 BRAVE 凝胶 PCC 和患者来源的癌症相关成纤维细胞 (PD-CAF)（主要肿瘤）共培养的机制基质细胞。该平台将提供有关加强矩阵必要性的直接实验证据 PCC 中细胞间串扰和 EMT 的研究。在目标 3 中，我们将开发具有梯度刚度的 BRAVE 凝胶来探究 PCC 在各种基质因素（例如细胞因子、CAF 和抑制剂）。结果将提供有关 PCC 迁移/侵袭和潜在分子靶点的见解对抗PCC转移。本提案中开发的 BRAVE 水凝胶和 durotaxis 装置将使我们能够回答许多难以解决的胰腺癌相关问题。此外，该项目的成果将对其他癌症的基础和应用研究以及定向研究产生影响干细胞分化用于组织再生。