Engineered Enteric Nervous System-Peri Neural Invasion platform to improve predictive preclinical screens in early-stage colorectal adenocarcinomas

工程肠神经系统-周围神经侵袭平台可改善早期结直肠腺癌的预测性临床前筛查

• 批准号: 10286742
• 负责人: Shreya Raghavan
• 金额: $ 21.97万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286742
• 关键词: 3-Dimensional; Address; Adjuvant; Adjuvant Chemotherapy; Adjuvant Therapy; Adult; Autologous; Biocompatible Materials; Biological Models; Biomedical Engineering; Clinical; Colon; Colorectal Adenocarcinoma; Colorectal Cancer; Colorectal Neoplasms; Dependence; Development; Engineering; Enteral; Enteric Nervous System; Epithelial Cell Proliferation; Epithelial Cells; Goals; Growth; Histopathologic Grade; Histopathology; In Vitro; Intestines; Malignant - descriptor; Malignant Neoplasms; Modeling; Nerve; Pathologic; Patients; Peripheral Nerves; Plant Roots; Pre-Clinical Model; Process; Prognosis; Publishing; Recruitment Activity; Regulation; Research Project Grants; Resistance; Risk Factors; Role; Sampling; Screening for cancer; System; Technology; Therapeutic; Tissue Engineering; Tumor Tissue; Tumor-Derived; Validation; Work; base; cancer recurrence; cancer stem cell; cellular engineering; chemotherapy; clinical decision-making; clinical practice; clinically significant; colon cancer patients; epithelial stem cell; high throughput screening; improved; innovation; nerve stem cell; new technology; novel; patient response; patient screening; perineural; personalized medicine; pre-clinical; progenitor; programs; relating to nervous system; response; screening; stem cell differentiation; stem cell self renewal; three-dimensional modeling; tool; tumor

PROJECT SUMMARY The objective of this proposal is to engineer and utilize enteric nerve plexi as a tool to improve predictive accuracy of preclinical screens in early stage II-III colorectal cancer (CRC). Peri-neural invasion (PNI) or CRC spread through nerves (especially nerves of the enteric nervous system; ENS) is an independent predictor of poor prognosis. Not only do CRC tumors actively recruit nerves, the ENS-nerves then have the ability to control epithelial cell proliferation and epithelial stem cell differentiation. This is noteworthy because both of these processes can alter CRC dynamics and modulate its response to adjuvant chemotherapy. In current clinical practice, PNI is established by pathological grading, but PNI into the ENS specifically is not considered. We believe that ENS-PNI is an important consideration in clinical decision making, because it could fundamentally alter tumor dynamics and response to adjuvant chemotherapy. Despite clear evidence that PNI is an active contributor to CRC, there are currently no preclinical models of ENS-PNI in CRC which severely limits our ability to investigate and target ENS-PNI. We propose to address this limitation through the development and validation of a novel 3D autologous patient-derived ENS-PNI platform, derived from patient-derived tumor epithelial cells and engineered nerves from adult enteric neural stem cells (ENSCs). We hypothesize that the engineered ENS-PNI platform can predict patient response to adjuvant chemotherapy with high fidelity via ENS regulation of CRC dynamics and cancer stem cell self-renewal. This proposal uniquely leverages the PI’s (Raghavan) published expertise with advanced biomaterial and bioengineered based platforms for engineering the tumor and colon microenvironment, combined with the Co-I’s (Esnaola) clinical expertise and access to patient biospecimen. Through our approach, we will examine the following aims: (1) Develop and validate an in vitro platform of ENS-PNI in CRC; (2) Utilize the engineered ENS-PNI platform to screen patient-derived early stage CRC tumors for adjuvant chemotherapy. We will validate the ENS-PNI platform using histopathology of the patient tumors they are derived from, and compare responses to chemotherapy to clinical responses. This will be the first instance of an in vitro 3D model of ENS-based PNI in CRC. The proposed work fits well into the Exploratory/Developmental Bioengineering Research Grant program, owing to its development of tissue- engineering based technology to improve the capability of preclinical cancer screening. This novel technology will be leveraged to develop a high-throughput amenable screen of stage II/III CRCs with a PNI component, for the purpose of identifying new avenues of targeted adjuvant therapy.

项目总结 这项建议目的是设计和利用肠神经丛作为一种工具来提高预测性 早期II-III期结直肠癌临床前筛查的准确性。神经周围侵袭(PNI)或CRC 通过神经(尤其是肠道神经系统的神经；ENS)传播是一种独立的预测因子 预后不良。结直肠癌不仅能主动招募神经，而且神经也有能力控制 上皮细胞增殖和上皮干细胞分化。这一点值得注意，因为这两个 化疗过程可以改变结直肠癌的动力学，调节其对辅助化疗的反应。在当前临床中 实践中，PNI是通过病理分级建立的，但不考虑具体进入ENS的PNI。我们 认为ENS-PNI是临床决策中的一个重要考虑因素，因为它可以从根本上 改变肿瘤动力学和对辅助化疗的反应。尽管有明确证据表明PNI是一名活跃的 目前还没有临床前的结直肠癌ENS-PNI模型，这严重限制了我们的 有能力调查和瞄准ENS-PNI。我们建议通过开发和 一种新的患者来源的3D自体ENS-PNI平台的验证 成人肠神经干细胞(ENSCs)的上皮细胞和工程化神经。我们假设 工程化的ENS-PNI平台可以通过ENS高保真地预测患者对辅助化疗的反应 结直肠癌动态调控与肿瘤干细胞自我更新。这项提议独特地利用了PI的 (Raghavan)发表了先进生物材料和基于生物工程的工程平台的专业知识 肿瘤和结肠微环境，结合Co-I‘s(埃斯诺拉)的临床专业知识和获得 病人的生物显微镜。通过我们的方法，我们将检查以下目标：(1)开发和验证In 结直肠癌ENS-PNI的体外平台；(2)利用工程ENS-PNI平台进行患者来源的早期筛选 将结直肠癌分期为辅助化疗。我们将使用组织病理学来验证ENS-PNI平台 并将化疗反应与临床反应进行比较。这 将是结直肠癌中基于ENS的PNI的体外3D模型的第一个实例。拟议的工作非常适合于 探索性/开发性生物工程研究资助计划，由于其开发的组织- 以工程技术为基础，提高临床前癌症筛查能力。这项新技术 将被用来开发具有PNI组件的第二/第三阶段CRC的高通量可服从屏幕，用于 确定靶向辅助治疗的新途径的目的。