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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.

项目总结