# Microbiome-derived regulators of therapy-resistant colorectal tumors

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2022 · $218,550

## Abstract

PROJECT SUMMARY
Colorectal cancer (CRC) is the third most deadly cancer for both men and women in the U.S. Despite effective
treatments for early-stage CRC, late-stage solid tumors exhibiting hypoxic and/or poor vascularization are more
difficult to treat. To improve the prognosis for these tumors, new treatment regimes for CRC are urgently needed.
Intestinal tract bacterial communities (microbiota) present a possible solution. Evidence from our team, as well
as others, indicates small molecule metabolites produced via metabolic processes of the microbiota can
promote, and in some cases inhibit, CRC tumorigenesis. These findings have suggested the possibility of
“Bacterial-derived Metabolite Therapy (BdMT)” as a transformative treatment of resistant CRC tumors. However,
our understanding of these tumor-microbe interactions is only in its infancy, and more work is needed to make
BdMT a reality. In particular, we lack knowledge on the identity of microbe-derived metabolites that regulate
CRC tumors, and also the underlying molecular mechanisms by which these molecules regulate the tumor cells.
In order to fill in these gaps, we use a powerful preclinical experimental model system (tumoroids) for assaying
physiological effects of microbe-derived metabolites on tumor cells, coupled with cutting-edge multi-omic
analysis tools to investigate molecular mechanisms of tumor response and identify their small molecular
regulators. Our hypothesis is that CRC tumoroids treated with metabolite fractions obtained from fecal samples
of CRC patients and analyzed via multi-omics will reveal microbiome-derived small molecule tumor regulators
which can be further leveraged for therapeutic applications. We will test this hypothesis via these Specific Aims:
Aim 1. Establish a CRC tumoroid model and test tumor cell response to fecal metabolite fractions.
Leveraging the expertise of PI Subramanian, we will establish patient-derived CRC tumoroids, and treat these
with metabolite fractions isolated from fecal samples of CRC patients and healthy controls. Tumor cell
proliferation will be assayed for each fraction tested; Aim 2. Identify and validate molecular regulators and
mechanisms of CRC tumoroid response using multi-omics. For metabolite fractions eliciting proliferative
tumor cell response in Aim 1, advanced multi-omic analysis will be performed on the tumor cells to investigate
response mechanisms. Metatranscriptomic analysis of fecal samples will identify microbiota functional pathways
active in tumor-bearing patients. Tumor response mechanisms and active microbial metabolic pathways will be
used to predict potential small molecule regulators active in the fecal fractions. Mass spectrometry-based
metabolomics will identify potential small molecule tumor regulators. Enabled by the diverse expertise of our
team in cancer microbiology, tumor-microbe interactions and multi-omic analysis, we will identify potential new
tumor-regulating metabolites for further investigat...

## Key facts

- **NIH application ID:** 10352947
- **Project number:** 1R21CA267707-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** TIMOTHY J. GRIFFIN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $218,550
- **Award type:** 1
- **Project period:** 2022-08-09 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352947

## Citation

> US National Institutes of Health, RePORTER application 10352947, Microbiome-derived regulators of therapy-resistant colorectal tumors (1R21CA267707-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10352947. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*