Dataset Information

Integrative Metatranscriptomic Analysis Reveals Disease-specific Microbiome-host Interactions in Oral Squamous Cell Carcinoma.

ABSTRACT: Studies on the microbiome of oral squamous cell carcinoma (OSCC) have been limited to 16S rRNA gene sequencing. Here, laser microdissection coupled with brute-force, deep metatranscriptome sequencing was employed to simultaneously characterize the microbiome and host transcriptomes and predict their interaction in OSCC. The analysis involved 20 HPV16/18-negative OSCC tumor/adjacent normal tissue pairs (TT and ANT) along with deep tongue scrapings from 20 matched healthy controls (HC). Standard bioinformatic tools coupled with in-house algorithms were used to map, analyze, and integrate microbial and host data. Host transcriptome analysis identified enrichment of known cancer-related gene sets, not only in TT versus ANT and HC, but also in the ANT versus HC contrast, consistent with field cancerization. Microbial analysis identified a low abundance yet transcriptionally active, unique multi-kingdom microbiome in OSCC tissues predominated by bacteria and bacteriophages. HC showed a different taxonomic profile yet shared major microbial enzyme classes and pathways with TT/ANT, consistent with functional redundancy. Key taxa enriched in TT/ANT compared with HC were Cutibacterium acnes, Malassezia restricta, Human Herpes Virus 6B, and bacteriophage Yuavirus. Functionally, hyaluronate lyase was overexpressed by C. acnes in TT/ANT. Microbiome-host data integration revealed that OSCC-enriched taxa were associated with upregulation of proliferation-related pathways. In a preliminary in vitro validation experiment, infection of SCC25 oral cancer cells with C. acnes resulted in upregulation of MYC expression. The study provides a new insight into potential mechanisms by which the microbiome can contribute to oral carcinogenesis, which can be validated in future experimental studies.

Significance

Studies have shown that a distinct microbiome is associated with OSCC, but how the microbiome functions within the tumor interacts with the host cells remains unclear. By simultaneously characterizing the microbial and host transcriptomes in OSCC and control tissues, the study provides novel insights into microbiome-host interactions in OSCC which can be validated in future mechanistic studies.

SUBMITTER: Jain V

PROVIDER: S-EPMC10166004 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Integrative Metatranscriptomic Analysis Reveals Disease-specific Microbiome-host Interactions in Oral Squamous Cell Carcinoma.

Jain Vinay V Baraniya Divyashri D El-Hadedy Doaa E DE Chen Tsute T Slifker Michael M Alakwaa Fadhl F Cai Kathy Q KQ Chitrala Kumaraswamy N KN Fundakowski Christopher C Al-Hebshi Nezar N NN

Cancer research communications 20230508 5

Studies on the microbiome of oral squamous cell carcinoma (OSCC) have been limited to 16S rRNA gene sequencing. Here, laser microdissection coupled with brute-force, deep metatranscriptome sequencing was employed to simultaneously characterize the microbiome and host transcriptomes and predict their interaction in OSCC. The analysis involved 20 HPV16/18-negative OSCC tumor/adjacent normal tissue pairs (TT and ANT) along with deep tongue scrapings from 20 matched healthy controls (HC). Standard b ...[more]

PMID: 37377901

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Project description:ObjectiveThis study aims to investigate the regulation of host gene transcription and microbial changes during the development of oral squamous cell carcinoma (OSCC) associated with smoking.MethodsThe OSCC mouse model and smoking mouse model were established using 200 μg/mL 4-nitroquinoline-1-oxide (4NQO) in drinking water and exposure to cigarette smoke (four cigarettes per session, once a day, 5 days a week). Tongue tissues were harvested at 4 weeks and 16 weeks. Histopathological changes were evaluated using hematoxylin and eosin staining and Ki67 staining. RNA sequencing was performed on the mouse tongue tissues to identify differentially expressed genes (DEGs), and the results were validated by RT-PCR and immunohistochemistry. 16S rDNA sequencing was used to analyze changes in the oral microbiota during the early development of OSCC, identifying differentially abundant taxa associated with smoking. Finally, associations between the relative abundances of the oral microbiome and host gene expression were modeled using the Origin software.ResultsDEGs associated with smoking during the development of OSCC were identified. There were 12 upregulated genes, including NR4A3 and PPP1R3C, and 23 downregulated genes, including CD74 and ANKRD1. These genes were enriched in functions related to the signal transduction of cellular processes such as inflammation, differentiation, immunity, and PI3K/AKT, NF-κB signaling pathways. 4NQO and smoking treatment decreased oral microbial diversity and reduced the abundance of Bacteroidetes, Proteobacteria, and Lactobacillus but increased the abundance of Staphylococcus. Integrative analysis showed that the expression of CD74 was positively correlated with the relative abundance of Lactobacillus, while PPP1R3C was negatively correlated with Bacteroidota.ConclusionIn addition to characterizing host gene expression and the oral microbiome, our study explored the potential role of host-microbiome interactions in the development of OSCC. These findings enhance our understanding of smoking-related OSCC occurrence and development, providing new insights for its prevention.

Project description:Oral squamous cell carcinoma (OSCC) is a prevalent malignancy in the oral-maxillofacial region with a poor prognosis. Oral microbiomes play a potential role in the pathogenesis of this disease. However, findings from individual studies have been inconsistent, and a comprehensive understanding of OSCC-associated microbiome dysbiosis remains elusive. Here, we conducted a large-scale meta-analysis by integrating 11 publicly available data sets comprising salivary microbiome profiles of OSCC patients and healthy controls. After correcting for batch effects, we observed significantly elevated alpha diversity and distinct beta-diversity patterns in the OSCC salivary microbiome compared to healthy controls. Leveraging random effects models, we identified robust microbial signatures associated with OSCC across data sets, including enrichment of taxa such as Streptococcus, Lactobacillus, Prevotella, Bulleidia moorei, and Haemophilus in OSCC samples. The machine learning models constructed from these microbial markers accurately predicted OSCC status, highlighting their potential as non-invasive diagnostic biomarkers. Intriguingly, our analyses revealed that the age- and gender-associated signatures in normal saliva microbiome were disrupted in the OSCC, suggesting perturbations in the intricate host-microbe interactions. Collectively, our findings uncovered complex alterations in the oral microbiome in OSCC, providing novel insights into disease etiology and paving the way for microbiome-based diagnostic and therapeutic strategies. Given that the salivary microbiome can reflect the overall health status of the host and that saliva sampling is a safe, non-invasive approach, it may be worthwhile to conduct broader screening of the salivary microbiome in high-risk OSCC populations as implications for early detection.ImportanceThe oral cavity hosts a diverse microbial community that plays a crucial role in systemic and oral health. Accumulated research has investigated significant differences in the saliva microbiota associated with oral cancer, suggesting that microbiome dysbiosis may contribute to the pathogenesis of oral squamous cell carcinoma (OSCC). However, the specific microbial alterations linked to OSCC remain controversial. This meta-analysis reveals robust salivary microbiome alterations. Machine learning models using differential operational taxonomic units accurately predicted OSCC status, highlighting the potential of the salivary microbiome as a non-invasive diagnostic biomarker. Interestingly, age- and gender-associated signatures in the normal salivary microbiome were disrupted in OSCC, suggesting perturbations in host-microbe interactions.

Project description:Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck worldwide. Dysbiosis of the microbiome has increasingly been linked to the development of different kinds of cancer. Applying 16S rRNA gene sequence analysis and metatranscriptomic analyses, we characterized the longitudinal changes in the profiles and the function of the oral microbiome in a 4-nitroquinoline-1-oxide (4-NQO)-induced model of OSCC in gnotobiotic mice. We characterized the dynamics of the oral microbiome in this model using two different microbiome inocula: one from healthy mice and the other from mice bearing a 4-NQO-induced tumor. Mice colonized with different oral microbiomes and exposed to 4-NQO had increased tumor numbers and sizes compared to controls exposed to 4-NQO but lacking a microbiome. We observed an overall increase in diversity in the tumorigenic samples compared to that in the nontumor group not exposed to 4-NQO. Despite the variability in community dynamics, specific patterns emerged during the progression of the disease. In the two groups that were inoculated with the OSCC-associated microbiome, we observed opposite profiles of abundance in Parabacteroides and Corynebacterium While the percentage of Parabacteroides bacteria decreased in the control group, it increased in the OSCC group, and the opposite was observed for Corynebacterium The metatranscriptomic analysis revealed overexpression of the same metabolic signatures associated with OSCC regardless of the community profile. These included nitrogen transport, response to stress, interspecies interactions, Wnt pathway modulation, and amino acid and lipid biosynthesis. Thus, these results seem to suggest that certain collective physiological activities are critical for microbiome-mediated OSCC progression.IMPORTANCE There is growing evidence that changes in the microbiome are associated with carcinogenesis. To date, no consistent oral microbiome composition associated with OSCC has been identified. Longitudinal and functional studies like the study presented here should yield a better understanding of the role that the oral microbiome plays in OSCC. Our findings, obtained using a germ-free mouse model, indicate that the presence of different oral microbiomes enhances tumorigenesis and increases the final number of tumors in mice. By studying community-wide expression profiles, we found that regardless of the phylogenetic composition of the microbiome, the same metabolic activities were consistently associated with OSCC. Therefore, due to the functional redundancy of the microbiome, the critical element in explaining the contribution of the microbiota in OSCC is the collective physiological activity of the community, thus accounting for the previous inability to identify a consensus community profile or etiologic agents for OSCC.

Dataset Information

Integrative Metatranscriptomic Analysis Reveals Disease-specific Microbiome-host Interactions in Oral Squamous Cell Carcinoma.

Significance

Publications

Integrative Metatranscriptomic Analysis Reveals Disease-specific Microbiome-host Interactions in Oral Squamous Cell Carcinoma.

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