# HBD-3: A novel factor orchestrating microbial persistence in suspicious oral lesions

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $193,135

## Abstract

ABSTRACT:
 Oral squamous cell carcinoma (OSCC) claims the lives of thousands in the U.S. and hundreds of
thousands worldwide annually. We have reported that an altered expression profile of hBD-3, an epithelial cell
derived antimicrobial peptide (AMP) and hBD-2, another epithelial cell AMP, is an early event in OSCC, and that
the ratio of hBD-3 and -2 in the lesion, when compared to the contralateral site, could be exploited in
distinguishing OSCC from other lesions in the oral cavity. We refer to this ratio as the beta defensin index
(BDI). Our ongoing clinical study of 81 subjects with oral lesions demonstrated high sensitivity (94%) and
specificity (97%) of BDI in distinguishing cancerous from benign oral lesions (P<0.0001).
 There has been a surge in microbiome studies over the last several years in attempts to discover
signature microbes with various cancers and their links to cancer progression, including OSCC. A common
theme arising from these studies is that the genus Fusobacterium, and specifically the oral commensal species
Fusobacterium nucleatum and F. periodonticum are enriched in OSCC when compared to contralateral normal
sites in the same patient. F. nucleatum also has demonstrated tumorigenic properties and has been shown to
induce tumor progression in an oral cancer murine model. We and others have shown that, while hBD-3 is a
potent AMP with a broad spectrum of activity, there is differential resistance of various oral microorganisms to
hBD-3. Most recently, we discovered that F. nucleatum demonstrates strain specific resistance to hBD-3 and
have identified a unique strategy that these organisms use to protect themselves from electrostatic disruption of
their outer membranes by hBDs. We now hypothesize that overexpression of hBD-3 in the context of OSCC
promotes selective persistence of key pathobionts, such as hBD-3-resistant Fusobacterium. To address
this hypothesis, our interdisciplinary team proposes the following two aims: Aim 1. Correlate BDI scores with
the outcome of a 16S rRNA gene-based microbiome study in OSCC vs. contralateral sites and vs. non-
OSCC lesions. Aim 2. Identify cultivable fusobacterial isolates resistant to hBD-3 in lesions vs.
contralateral sites.
 Ours is the first study to pin-point a specific OSCC-derived agent; i.e., hBD-3, that can contribute
to compositional shifting of the microbiota in cancerous vs. non-cancerous oral lesions. We surmise that
high BDI scores will dictate the persistence of signature hBD3-resistant fusobacteria in OSCC lesions when
compared to contralateral normal sites and non-OSCC lesions.
 Results obtained from this proposal will lead to future studies to (1) determine the utility of bacterial
signatures as cancer biomarkers, (2) identify genomic determinants of hBD resistance and (3) decipher the
organisms’ pathogenic properties in promoting cancer progression.

## Key facts

- **NIH application ID:** 9983695
- **Project number:** 5R21DE028416-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** AARON WEINBERG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,135
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983695

## Citation

> US National Institutes of Health, RePORTER application 9983695, HBD-3: A novel factor orchestrating microbial persistence in suspicious oral lesions (5R21DE028416-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983695. Licensed CC0.

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