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A dysbiotic microbiome promotes head and neck squamous cell carcinoma

Oncogene volume 41, pages 1269–1280 (2022)Cite this article

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Abstract

Recent studies have reported dysbiotic oral microbiota and tumor-resident bacteria in human head and neck squamous cell carcinoma (HNSCC). We aimed to identify and validate oral microbial signatures in treatment-naïve HNSCC patients compared with healthy control subjects. We confirm earlier reports that the relative abundances of Lactobacillus spp. and Neisseria spp. are elevated and diminished, respectively, in human HNSCC. In parallel, we examined the disease-modifying effects of microbiota in HNSCC, through both antibiotic depletion of microbiota in an induced HNSCC mouse model (4-Nitroquinoline 1-oxide, 4NQO) and reconstitution of tumor-associated microbiota in a germ-free orthotopic mouse model. We demonstrate that depletion of microbiota delays oral tumorigenesis, while microbiota transfer from mice with oral cancer accelerates tumorigenesis. Enrichment of Lactobacillus spp. was also observed in murine HNSCC, and activation of the aryl-hydrocarbon receptor was documented in both murine and human tumors. Together, our findings support the hypothesis that dysbiosis promotes HNSCC development.

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Fig. 1: Oral microbiotas differ between HNSCC cases and non-HNSCC controls.
Fig. 2: Alpha-diversity indices differ between HNSCC cases and non-HNSCC controls.
Fig. 3: Differentially abundant taxa between HNSCC cases and non-HNSCC controls.
Fig. 4: Overlap in taxa differentially abundant between non-HNSCC controls and different tumor locations.
Fig. 5: Differential abundance of Lactobacillus and Neisseria species in HNSCC cases and controls.
Fig. 6: Reduced tongue tumor formation and size upon antibiotic (Abx) treatment.
Fig. 7: Aryl-hydrocarbon Receptor (AhR) expression in human and murine HNSCC.
Fig. 8: Effects of microbiome on tongue tumor development in germ-free and reconstitution conditions.

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Data availability

Demultiplexed 16 S rRNA paired-end sequence data and associated metadata were deposited in the NCBI Sequence Read Archive under BioProject ID PRJNA749451. All other data supporting the findings of this study are available within the paper and its supplementary files or are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was funded by grants from NIH-NIDCR (R56 DE028959; SLL & DNF), NIH-NIAMS (R01 AR075033; KAK), the Cancer League of Colorado (SLL & DNF), Golfers Against Cancer (SLL & DNF), and the University of Colorado Cancer Center (SLL & DNF). DNF, CER, and JMK were supported in part by the University of Colorado GI and Liver Innate Immunity Program. VRR was supported in part by a Career Development Grant from the University of Colorado Cancer Center and NIH-NIDCD K23 DC014747 (VRR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations.

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, CO, USA

    Daniel N. Frank, Jennifer M. Kofonow & Charles E. Robertson

  2. Department of Otolaryngology—Head & Neck Surgery, University of Colorado Anschutz Medical Center, Aurora, CO, USA

    Yue Qiu, Yu Cao, Shuguang Zhang, Ling Lu, Yanqiu Liu, Haibo Wang, John Song, Vijay R. Ramakrishnan & Shi-Long Lu

  3. Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, 110122, China

    Yue Qiu

  4. Department of Surgical Oncology, The First University Hospital, China Medical University, Shenyang, 110122, China

    Yu Cao

  5. Division of Rheumatology and the Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, CO, USA

    Cassandra L. Levens & Kristine A. Kuhn

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  1. Daniel N. Frank
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Contributions

Conceptualization: DNF, JS, VRR, SLL. Acquisition, analysis, or interpretation of data: DNF, YQ, SZ, LL, JMK, CER, YL, HW, CLL, KAK, JS, VRR, SLL. Original manuscript preparation: DNF, SLL. Manuscript editing: all authors.

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Frank, D.N., Qiu, Y., Cao, Y. et al. A dysbiotic microbiome promotes head and neck squamous cell carcinoma. Oncogene 41, 1269–1280 (2022). https://doi.org/10.1038/s41388-021-02137-1

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