The microbiome associated with oral Leukoplakia: A multi-omics mechanistic study

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Project Summary There is increasing interest in the role of the microbiome in the development and/or progression of various cancers including oral squamous cell carcinoma (OSCC). Research has shown that OSCC is associated with a distinct microbiome. However, OSCC in itself represents a late stage in a disease process in which the observed microbial changes are as likely to be passenger or, at best, late driving events. To better understand the role of the microbiome in OSCC and identify microbial biomarkers for early detection and prevention, it is crucial to assess the microbiome in early stages of the disease, e.g. oral potentially malignant disorders (OPMDs). Oral leukoplakia (OL; the focus of this study) is the most common OPMD. Little is known about the microbiome associated with OPMDs, its role in their progression, or its potential as non-invasive diagnostic biomarker to complement oral epithelial dysplasia grading, currently the best available indicator. Our long-term goal is to identify diagnostic/prognostic microbial biomarkers of OPMDs and determine the effect of the microbiome on oral carcinogenesis by conducting a large-scale, international consortium study in two phases: a case-control study (this application) to comprehensively study the dysbiotic microbiome associated with OL/dysplasia in a North American population; followed by a longitudinal study (future application) that will involve following up the same and additional cohorts of OPMDs to identify/validate microbiome biomarkers of malignant transformation (MT). Our hypothesis is that shifts in microbiome composition and function associated with OL represent early driver events that correlate with the severity of dysplasia and contribute to the progression of oral cancer. In addition, we also hypothesize that oncogenic strains of oral microorganisms could be driving these disorders. To address these hypotheses, we propose 3 specific aims: 1) Characterize the composition of the multi-kingdom microbiome associated with OL and the different grades of dysplasia; 2) Define both microbial and host transcriptomes in OL and potential interactions between these two segments of the metatranscriptome. 3) Assess in vitro the oncogenic properties of bacterial and fungal strains isolated from OL. The study will be conducted by a team of international experts and will enroll 210 OL patients, 105 OSCC patients, and 420 healthy control subjects (735 subjects in total) to be recruited in two study centers. One-thousand and five hundred saliva and swab samples will be analyzed using shotgun metagenomic and metatranscriptome analysis. Furthermore, 36 bacterial/fungal strains previous isolated from OL patients with different grades of dysplasia will be screened for their effect on proliferation, invasion, epithelial-mesenchymal transition and cytokine and matrix metalloproteinases production by normal and dysplastic epithelial cells in vitro. The study will establish the role of the microbiome in the early stages of oral carcinogenesis, and identify microbial biomarkers of OL and dysplasia, which in a subsequent study can be validated as biomarkers of MT.