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

基本信息

批准号：
10439886
负责人：
Shreya Raghavan
金额：
$ 16.93万
依托单位：
TEXAS ENGINEERING EXPERIMENT STATION
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：
2021-07-01 至 2024-06-30
项目状态：
已结题

项目摘要

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.

项目摘要该建议的目的是设计并利用肠神经plexi作为提高预测性的工具临床前筛选早期II-III III结直肠癌（CRC）的准确性。神经周围入侵（PNI）或CRC 通过神经传播（尤其是肠神经系统的神经； ENS）是独立的预测指标预后不良。 CRC肿瘤不仅会积极募集神经，而且具有控制能力上皮细胞增殖和上皮干细胞分化。这是值得注意的，因为这两个过程可以改变CRC动力学并调节其对化疗的反应。在当前的临床上实践，PNI是通过病理分级确定的，但是不考虑PNI进入ENS。我们认为ENS-PNI是临床决策中的重要考虑因素，因为它可以从根本上改变肿瘤动力学和调整化疗的反应。尽管有明确的证据表明PNI是活跃的 CRC的贡献者，目前没有CRC中ENS-PNI的临床前模型严重限制了我们的调查和靶向ENS-PNI的能力。我们建议通过开发来解决这一限制，新型3D自体衍生的ENS-PNI平台的验证，该平台源自患者衍生的肿瘤来自成人肠神经元干细胞（ENSC）的上皮细胞和工程神经。我们假设设计的ENS-PNI平台可以通过ENS预测患者对使用高保真度调整化学疗法的反应调节CRC动力学和癌症干细胞自我更新。该提案独特地利用了PI的（Raghavan）发表了具有高级生物材料和生物工程平台的工程专业知识肿瘤和结肠微环境，结合了Co-I（Esnaola）的临床专业知识和进入患者生物偶数。通过我们的方法，我们将研究以下目的：（1）开发和验证一个 CRC中ENS-PNI的体外平台；（2）利用工程的ENS-PNI平台来筛选患者衍生的早期用于调整化疗的CRC肿瘤。我们将使用组织病理学来验证ENS-PNI平台它们衍生自患者肿瘤，并将对化学疗法的反应与临床反应进行比较。这将是CRC中ENS基PNI的体外3D模型的第一个实例。拟议的工作非常适合探索性/发展性生物工程研究赠款计划，由于其组织的发展基于工程的技术来提高临床前癌筛查的能力。这项新技术将利用具有PNI组件的II/III级CRC的高通量的屏幕，用于识别有针对性调整疗法的新途径的目的。