Abstract
Oral squamous cell carcinoma (OSCC) has high mortality rates that are largely associated with lymph node metastasis. However, the molecular mechanisms that drive OSCC metastasis are unknown. Extracellular vesicles (EVs) are membrane-bound particles that play a role in intercellular communication and impact cancer development and progression. Thus, profiling EVs would be of great significance to decipher their role in OSCC metastasis. For that purpose, we used a reductionist approach to map the proteomic, miRNA, metabolomic, and lipidomic profiles of EVs derived from human primary tumor (SCC-9) cells and matched lymph node metastatic (LN1) cells. Distinct omics profiles were associated with the metastatic phenotype, including 670 proteins, 217 miRNAs, 26 metabolites, and 63 lipids differentially abundant between LN1 cell– and SCC-9 cell–derived EVs. A multi-omics integration identified 11 ‘hub proteins’ significantly decreased at the metastatic site compared with primary tumor–derived EVs. We confirmed the validity of these findings with analysis of data from multiple public databases and found that low abundance of seven ‘hub proteins’ in EVs from metastatic lymph nodes (ALDH7A1, CAD, CANT1, GOT1, MTHFD1, PYGB, and SARS) is correlated with reduced survival and tumor aggressiveness in patients with cancer. In summary, this multi-omics approach identified proteins transported by EVs that are associated with metastasis and which may potentially serve as prognostic markers in OSCC.
Highlights
Proteomic, miRNA, metabolomic, and lipidomic profiles were mapped in oral cancer extracellular vesicle (EV). The molecular profile of Extracellular vesicles (EVs) was associated with the lymph node metastatic phenotype. A multi-omics integrative analysis revealed 11 highly connected ‘hub proteins.’ ‘Hub proteins’ from EVs are candidates as prognostic markers in oral cancer
We investigated the differences between the molecular repertoire of EVs released by primary tumor (SCC-9) and metastatic cells (LN1), both derived from Oral squamous cell carcinoma (OSCC) of the tongue, using a multi-omics approach followed by integrative analysis (Fig. 1A)
Emerging evidences indicate that tumor-derived EVs can play a role in the metastatic process [9, 10, 13], and detection of changes within vesicle cargoes is of special interest for cancer diagnosis, prognosis, and monitoring [57]
Summary
To avoid reducing the number of differentially abundant molecules and failing to perform process enrichment and the multi-omics analysis, we considered a nonadjusted p-value obtained from Student's t test and filtered out the proteins, miRNA, lipids, or metabolites using other strategies, like (i) filtering the datasets by a minimum of two processing replicates in at least one condition; (ii) performing the integrative analysis of the multiomics, and (iii) for the proteomes, carrying out a comprehensive search of prognostic markers using public databases.
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