# Supplemental Funds for K22 Establishing the molecular and cellular mechanisms of Lgr5 signaling for controlling cancer stem cell behavior

> **NIH NIH K22** · DUKE UNIVERSITY · 2020 · $54,000

## Abstract

ABSTRACT (original parent award).
Colon cancer is the second leading cause of cancer deaths among men and women combined.
Therefore, alternative therapies are of critical need. In normal tissue, intestinal stem cells act to
enable renewal of the entire epithelium every week. It is now known that the transformation of
stem cells into colon cancer stem cells is a major inciting event that underlies carcinogenesis.
Cancer stem cells are tumor-initiating cells, are refractory to therapy, and are linked to the very
poor prognosis associated with late-stage colon cancer diagnosis. Better therapies may result if
colon cancer stem cells could be eliminated. However, eradicating this population of cells is an
extremely challenging problem, due to the intrinsic capacity of colon cancer stem cells to be long-
lived, self-renewing, and highly proliferative. One proposed solution to this problem is to
pharmacologically bias cancer stem cell fate toward a terminally differentiated cell fate. In other
words, drive cancer stem cells to adopt a cell fate that does not proliferate, that has a short life
expectancy, and that is sensitive to chemotherapy. Realization of this differentiation therapy
requires that the identity of the cancer stem cell be known and that a candidate molecular target
exists for a therapeutic entry point. To this end, the leucine-rich G protein coupled receptor-5
(Lgr5) has been found to act as a marker for colon cancer stem cells and is a tantalizing
pharmacological target. Lgr5, together with its homologue Lgr4, act as modulators for the
Wnt/ßcatenin signaling pathway. Wnt/ßcatenin signaling is a critical pathway that regulates stem
cell homeostasis in the intestine. Mutations in this pathway result in excessive signaling and
strongly bias stem cell behavior toward that of a long-lived and highly proliferative cancer stem
cell. Lgr5 is therefore an attractive pharmacological target for counteracting this imbalance and
restoring normal cell fate dynamics. However, the mechanisms of Lgr5-signaling and its roles in
vivo are still vague and represent a major knowledge gap. Therefore, the objective of this
proposal will be to determine how Lgr5-signaling controls stem and cancer stem cell fate. To
accomplish this objective, I will test the central hypothesis that inhibition of Lgr5 internalization
attenuates Wnt/ßcatenin signaling and promotes cancer stem cell differentiation. Three specific
aims have been proposed to test this hypothesis and will in (Aim 1) Clarify the mechanism of
Lgr5-mediated Wnt/ßcatenin signaling, (Aim 2) Elucidate Lgr5-dependent signaling
mechanisms coordinating stem cell behavior, and (Aim 3) Identify small molecule
interventions for driving cancer stem cell differentiation.

## Key facts

- **NIH application ID:** 10127902
- **Project number:** 3K22CA212058-03S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Joshua Clair Snyder
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $54,000
- **Award type:** 3
- **Project period:** 2020-05-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127902

## Citation

> US National Institutes of Health, RePORTER application 10127902, Supplemental Funds for K22 Establishing the molecular and cellular mechanisms of Lgr5 signaling for controlling cancer stem cell behavior (3K22CA212058-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10127902. Licensed CC0.

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