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

> **NIH NIH R21** · TEXAS ENGINEERING EXPERIMENT STATION · 2022 · $169,272

## Abstract

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.

## Key facts

- **NIH application ID:** 10439886
- **Project number:** 5R21CA263768-02
- **Recipient organization:** TEXAS ENGINEERING EXPERIMENT STATION
- **Principal Investigator:** Shreya A. Raghavan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $169,272
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439886

## Citation

> US National Institutes of Health, RePORTER application 10439886, Engineered Enteric Nervous System-Peri Neural Invasion platform to improve predictive preclinical screens in early-stage colorectal adenocarcinomas (5R21CA263768-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10439886. Licensed CC0.

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