# The Functional Role of LGR5 in Colon Cancer

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $356,850

## Abstract

Abstract
 Colorectal cancer is the second leading cause of cancer mortality in the US, in part due
to the lack of effective therapies for advanced disease. Thus, there is an urgent need to identify
molecules/pathways involved in oncogenic transformation and progression for cancer treatment.
 LGR5 has been discovered as a proliferating adult stem cell marker in the small
intestine. It has been reported that, after binding R-spondins, LGR5 forms a physical complex
with the Wnt receptor Frizzled and its co-receptor LRP6 to amplify Wnt canonical signaling. In
addition, LGR5 expression has been shown to be upregulated in colon cancer as compared to
normal tissues. Therefore, LGR5 has been proposed to be a tumor promoter in the intestine and
colon. However, our studies of patient samples indicate that although expression of LGR5 is
higher in stage I/II adenocarcinomas than in normal crypts (* P < 0.05), its expression
decreases in stage III/IV tumors as compared to stage I/II tumors (** P < 0.01). These results
suggest that loss of LGR5 is associated with advanced stage cancer, which argues against a
promoting role, especially at later stages. We showed that LGR5 inhibits clonogenecity and
survival in colon cancer cells and that knockdown of LGR5 expression increases their
metastatic potential in an orthotopic model. Mechanistically, LGR5 activates TGFβ signaling,
which occurs even in the absence of TGFβ RII, and the presence of RII further enhances the
activation by LGR5. In addition, LGR5 inhibits Wnt signaling in a Smad4-dependent manner.
Our results point to a suppressive role of LGR5 in colon cancer progression/metastasis.
 In this proposal, we will determine the mechanism(s) by which LGR5 activates TGFβ
signaling and inhibits Wnt activation. We will also determine the functional role of LGR5 in colon
cancer development/progression using genetic mouse models, investigate whether restoration
of LGR5 expression elicits metastasis regression and whether LGR5 functions through the
activation of TGFβsignaling and/or inhibition of Wnt signaling in an orthotopic mouse model and
in patient specimens. The completion of these studies will identify RSPO/LGR5 /RI as a novel
TGFβ transduceome and a colon cancer metastasis suppressor and substantially advance our
understanding of the molecular mechanisms of LGR5, an intestinal stem cell marker, in
suppressing colon cancer progression and metastasis.

## Key facts

- **NIH application ID:** 10087899
- **Project number:** 5R01CA208063-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087899

## Citation

> US National Institutes of Health, RePORTER application 10087899, The Functional Role of LGR5 in Colon Cancer (5R01CA208063-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10087899. Licensed CC0.

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