# Exploring the Role of DMBT1 Suppression in Invasion of Oral Cancer

> **NIH NIH F30** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $54,774

## Abstract

PROJECT SUMMARY/ABSTRACT
 Squamous cell carcinoma (SCC), the most common oral cancer, notoriously recurs, leading to poor survival.
Invasion of cancer cells is essential for recurrence and progression, emphasizing the importance of investigating
mechanisms of invasion in order to improve patient survival. We recently identified a mechanism in which SCC
co-opts adjacent non-cancerous epithelium, referred to as cancer-associated keratinocytes (CAKs), to enhance
lateral invasion, which was associated with recurrence. Deleted in malignant brain tumors 1 (DMBT1), a tumor
suppressor, is downregulated in SCC to promote lateral invasion and formation of satellite lesions. In a feedback
loop, SCC-secreted transforming growth factor-beta (TGFβ) suppresses DMBT1 in CAKs; this causes CAKs to
release cytokines that enhance invasion of tumor cells away from the tumor bulk. The objective of the proposed
study is to understand how TGFβ suppresses DMBT1 in CAKs and why it does so. Interestingly, DMBT1 is also
an anti-microbial protein; preliminary data show that downregulation of DMBT1 in CAKs increases susceptibility
to Porphyromonas gingivalis, a keystone pathogen in periodontal disease. There is a strong correlation between
SCC and dysbiosis in the oral microbiome. Multiple studies have shown that P. gingivalis enhances SCC
invasion, but none have examined the ability of P. gingivalis to enhance SCC invasion via CAKs. Normal
keratinocytes infected with P. gingivalis secrete pro-inflammatory cytokines. The overall hypothesis is that
SCC-mediated suppression of DMBT1 in CAKs via TGFβ facilitates bacterial entry into CAKs, thereby
enhancing release of cytokines that promote invasion of SCC. To test this hypothesis, we propose two aims:
Aim #1: Characterize the molecular mechanism by which TGFβ suppresses DMBT1 in CAKs; and Aim #2:
Investigate the impact of DMBT1 suppression in CAKs on bacterial entry, release of pro-invasive cytokines, and
SCC invasion. To understand the mechanism of DMBT1 suppression in CAKs, we will use in genetic and
pharmacological approaches in cell lines. To understand the significance of DMBT1 suppression in CAKs on
SCC invasion, we will use high-throughput proteomics to investigate the secretome of CAKs, and genetic and
pharmacologic approaches to establish the role of these cytokines in invasion using in in vitro and in vivo models,
including Dmbt1-/- mice. Overall, this project will investigate the mechanism by which SCC co-opts CAKs to
promote the release of cytokines that enhance tumor invasion; this could provide therapeutic targets to prevent
SCC recurrence and improve survival.

## Key facts

- **NIH application ID:** 10908250
- **Project number:** 5F30DE031940-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Erika Bunnine Danella
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $54,774
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908250

## Citation

> US National Institutes of Health, RePORTER application 10908250, Exploring the Role of DMBT1 Suppression in Invasion of Oral Cancer (5F30DE031940-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10908250. Licensed CC0.

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