# Shaping of the Microenvironment in Colonic Pre-Cancer by Epithelia and Microbiota

> **NIH NIH U54** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $1,730,379

## Abstract

The Vanderbilt TBEL Center assembles a multi-disciplinary team of field-specific experts to collaboratively
investigate the basic and translational pathways of colonic pre-cancer progression. Our foundational work on
two subtypes of colonic pre-cancers, adenomas (ADs) and sessile serrated lesions (SSLs), depicts the early
origins of tumorigenesis that are shaped by modulation of the immune microenvironment via neoplastic cells and
the microbiota. We have shown that SSLs originate from gastric metaplasia arising from the mucosal surface in
a cytotoxic immune microenvironment, whereas ADs arise from stem cell-derived WNT activation at the crypt
base. In this center, we will extend our investigation of specific biological mechanisms towards the developmental
trajectories of these pre-malignant lesions into progression or indolence. Basic Project 1 investigates the
contribution of neutrophil-AD crosstalk, largely via dipeptidase 1 (DPEP1) both at the cell surface and released
in small extracellular vesicles, in the course of AD progression. Translational Project 2 investigates, in human
prospective studies, the association of pks+ Escherichia coli that induces genotoxic stress with pre-cancer
progression, as well as colon epithelial cell and mucosa mechanisms that may contribute to a polyp-promoting
microenvironment. Basic Project 3 investigates acquisition of stemness in modulating antigen presentation to
cytotoxic T cells in the context of co-evolution between neoplastic cells and the immune system. Joint analysis
of common colorectal pre-cancer tissues will facilitate an ongoing process of iteration and integration across all
projects. Our TBEL Center offers a complementary blend, from reductionist and systems biology approaches, to
investigate critical factors involved in the progression of pre-cancerous tumors of the colon to CRC. The work
will utilize cutting-edge technologies on human tissues, including single-cell and spatial transcriptomics, small
extracellular vesicle profiling, multiplex imaging, longitudinal data analysis, and next-generation computational
algorithms. In addition, substantial human polyp resources previously established by the Vanderbilt GI
Specialized Programs of Research Excellence and the NCI Moonshot Human Tumor Atlas Network will be
leveraged by the same team of investigators in the TBEL Center. In addition, an innovative co-culture system
will be employed by each project, where polarizing pre-cancer organoids can be co-cultured with key
microenvironment elements exposed to neoplastic cells from the luminal or basal side. This work will inform the
modeling of tumor development trajectories and identify mechanisms of progression that will enable
improvements in risk stratification, precision prevention, and interception for individuals with colorectal pre-
cancers.

## Key facts

- **NIH application ID:** 10518845
- **Project number:** 1U54CA274367-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ken S Lau
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,730,379
- **Award type:** 1
- **Project period:** 2022-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518845

## Citation

> US National Institutes of Health, RePORTER application 10518845, Shaping of the Microenvironment in Colonic Pre-Cancer by Epithelia and Microbiota (1U54CA274367-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10518845. Licensed CC0.

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