# Role of the Oral Microbiome in Oral Squamous Cell Carcinoma Progression

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $164,653

## Abstract

Project Abstract
Head and neck cancer represents the sixth most common malignancy worldwide, and oral squamous cell
carcinomas (OSCC) are the most frequent malignancies in the oral cavity. Despite improvements in prognosis
for many other human cancers, survival rates for OSCC have remained nearly unchanged for decades,
emphasizing the urgent need for new treatment modalities. Mounting evidence indicates that the human
microbiome plays a key role in promoting a variety of cancers, including stomach, colon and gall bladder, via
various mechanisms. In contrast to the lower GI tract, the role of, and mechanisms by which, the oral
microbiome may contribute to OSCC remain obscure. The impetus for this project is that gnotobiotic mouse
models, coupled with functional transcriptomics, offer powerful new approaches to elucidate the mechanisms
that underlie the tumorigenic effects of the oral microbiome in OSCC. In preliminary studies we found that
germfree mice colonized with microbiomes, and challenged with the carcinogen 4-NQO, developed many
more, and larger tumors than mice that remained germfree. Transcriptionally-hyperactive candidate pathogens
were identified, which expressed numerous virulence signatures, paralleling previous findings in human OSCC.
Tumor-infiltrating leukocytes (TIL) appeared to be modulated to an immunosuppressive vs protective
phenotype in microbiome-colonized mice. These findings lead to our central hypothesis, that key pathogenic
species in the oral microbiome promote OSCC progression, at least in part by inducing immunosuppression vs
protective immunity. This will be tested by determining the transcriptionally-hyperactive species that most
strongly promote the growth and metastasis of syngeneic mouse oral cancer (MOC) cell line orthografts in
mouse tongues in vivo. Bacterial metabolic pathways will be characterized by metatranscriptomics, and the
microbiome-modulated immune as well as tumor cell responses by RNASeq. Immune responses induced by
tumorigenic pathogens will be characterized locally and in draining lymph nodes. The function of Treg and
myeloid-derived suppressor cells will be evaluated by abrogation with immunotherapeutic antibodies in vivo.
Direct effects of tumorigenic pathogens on tumor cell growth and invasion will be determined. The goal is to
identify key oral tumorigenic bacteria and their molecular mechanisms that are responsible for promoting
OSCC progression. Successful completion of this project will suggest new microbiome-focused interventions to
reduce OSCC initiation and recurrence, and contribute to the development of next generation therapeutics for
this recalcitrant and devastating disease.

## Key facts

- **NIH application ID:** 9975819
- **Project number:** 5R21DE028063-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** PHILIP Stashenko
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $164,653
- **Award type:** 5
- **Project period:** 2019-07-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975819

## Citation

> US National Institutes of Health, RePORTER application 9975819, Role of the Oral Microbiome in Oral Squamous Cell Carcinoma Progression (5R21DE028063-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9975819. Licensed CC0.

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