A microengineered colon cancer-chip designed to investigate tumor-stromal interactions driving cancer progression

一种微工程结肠癌芯片，旨在研究驱动癌症进展的肿瘤-基质相互作用

基本信息

批准号：
10526189
负责人：
Shannon Michelle Mumenthaler
金额：
$ 35.5万
依托单位：
ELLISON INSTITUTE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10526189
关键词：
3-Dimensional Address Affect Automobile Driving Biochemical Biological Assay Biological Models Biomimetics Biopsy Blood Vessels Cancer Etiology Cancer Model Cancer Patient Cell Death Cell Proliferation Cells Cessation of life Cetuximab Characteristics Chemoresistance Clinical Coculture Techniques Collaborations Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Combination Drug Therapy Data Death Rate Digestion Disease Drug Monitoring Drug Screening Elements Endothelium Engineering Environment Epidermal Growth Factor Receptor Epithelial Fibroblasts Fluorouracil Functional disorder Gene Expression Profile Goals Heterogeneity Human Image Knowledge Leucovorin Malignant Neoplasms Measures Mechanics Membrane Microfluidic Microchips Microfluidics Modality Modeling Motion Nutrient Organ Organoids Pathway interactions Patients Periodicity Peristalsis Pharmaceutical Preparations Phenotype Physiological Positioning Attribute Pre-Clinical Model Research Personnel Role Sampling Seeds Stretching Stromal Cells Stromal Neoplasm Survival Rate System Technology Testing Therapeutic Tissue Engineering Tissues Treatment Efficacy Tumor Cell Invasion Tumor Tissue United States Vision Work anticancer research base behavioral response biobank cancer cell cell behavior cell type clinical material colorectal cancer progression confocal imaging density design drug development drug efficacy fluid flow human disease improved in vivo innovation insight irinotecan mass spectrometric imaging mechanical force metabolomics metastatic colorectal microphysiology system migration multidisciplinary mutant neoplastic cell new therapeutic target novel novel therapeutics organ on a chip pre-clinical prevent response screening shear stress standard of care targeted treatment transcriptomics treatment comparison treatment response treatment strategy tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Despite the introduction of novel therapies, the five-year survival rate for metastatic disease remains around 10%. To improve our understanding of tumor progression and drug efficacy, it is vital to develop preclinical tumor models that accurately reflect the native pathophysiology of CRC “ex vivo”. The complexities of the tumor microenvironment (TME), including stromal cell types and mechanical forces, are not fully reproduced in existing preclinical models. Microfluidic-based “organ-on-chip” technologies, which are designed to simulate the 3-D human organ environment both mechanically (e.g., fluid flow and cyclic deformation) and biochemically (e.g., nutrient digestion, secretion, transport), have recently provided researchers with greater insights into and expanded control over the TME. In this proposal, we are adapting the organ-on-chip technology to create human colon organ chips colonized with patient-derived CRC cells and stromal elements (endothelial and cancer- associated fibroblast (CAF) cells) in relevant tissue:tissue compartments with integrated microfluidics and stretching to mimic in vivo peristalsis-like motions. The goal is to create a physiologically relevant, organ- dependent tumor model that will allow for long-term culture and characterization of CRC cellular dynamics, and serve as a platform for testing specific therapeutic modalities to prevent or delay tumor progression. Using novel imaging assays and “omics” based approaches, we will evaluate the role of the physical (i.e., peristalsis) and cellular (CAFs) microenvironment in colon tumor progression. In Aim 1, we will develop patient- derived CRC-on-Chips incorporating primary normal and tumor epithelium to assess CRC tumor growth and early metastatic spread (i.e., invasion into the vascular channel) in the presence of cyclic stretch, mimicking peristalsis. In Aim 2, we will analyze the impact of the stromal CAF microenvironment on tumor cell behavior and examine the extent and role of inter-patient CAF functional heterogeneity. In Aim 3, we will assess the drug screening capabilities of the CRC-on-Chip platform via monitoring of drug-induced cellular responses, and determine whether drug responses on chips can predict patient clinical responses. The longer-term vision for developing a microengineered CRC model that more closely resembles human disease is to expedite the identification and screening of novel drug targets and innovative treatment strategies with a focus on disrupting tumor-stromal interactions. Our multi-disciplinary team with complementary expertise, the groundbreaking technologies, and availability of clinical materials put us in a prime position to successfully address important aspects of CRC tumorigenesis and advance our understanding of the tumor niche.

项目概要尽管结直肠癌（CRC）是美国癌症相关死亡的第二大原因。随着新疗法的推出，转移性疾病的五年生存率仍保持在 10% 左右。提高我们对肿瘤进展和药物疗效的理解，开发临床前肿瘤模型至关重要准确地反映了 CRC“离体”的天然病理生理学。微环境（TME），包括基质细胞类型和机械力，在现有的基于微流体的“器官芯片”技术，旨在模拟 3D 人体器官环境在机械上（例如，流体流动和循环变形）和生物化学上（例如，（营养消化、分泌、运输），最近为研究人员提供了更深入的见解扩大对 TME 的控制在这项提案中，我们正在采用芯片器官技术来创造人类。结肠器官芯片定植有患者来源的 CRC 细胞和基质成分（内皮细胞和癌症细胞）相关组织中的相关成纤维细胞（CAF）：具有集成微流体和拉伸以模仿体内蠕动状运动，目标是创造一个生理相关的器官。依赖性肿瘤模型，将允许长期培养和 CRC 细胞动力学表征，以及作为测试特定治疗方式以预防或延缓肿瘤进展的平台。使用新颖的成像分析和基于“组学”的方法，我们将评估物理的作用（即，结肠肿瘤进展中的蠕动）和细胞（CAF）微环境在目标 1 中，我们将开发患者- 衍生的 CRC-on-Chips 包含原发性正常上皮和肿瘤上皮，以评估 CRC 肿瘤生长和在存在循环拉伸的情况下早期转移扩散（即侵入血管通道），模仿在目标 2 中，我们将分析基质 CAF 微环境对肿瘤细胞行为和蠕动的影响。检查患者间 CAF 功能异质性的程度和作用在目标 3 中，我们将评估药物。通过监测药物诱导的细胞反应，实现 CRC-on-Chip 平台的筛选能力，以及确定芯片上的药物反应是否可以预测患者的临床反应。开发一种更类似于人类疾病的微工程结直肠癌模型是为了加快识别和筛选新的药物靶点和创新的治疗策略，重点是破坏我们的多学科团队具有互补的专业知识，具有开创性。技术和临床材料的可用性使我们处于成功解决重要问题的首要地位结直肠癌肿瘤发生的各个方面，并增进我们对肿瘤生态位的理解。