Multi - Omics Analysis Of Migrasomes In Oral Leukoplakia Carcinogenesis

Oral leukoplakia (OLK), a recognized oral potentially malignant disorder, demonstrates significant susceptibility to malignant transformation into oral squamous cell carcinoma (OSCC). This study aimed to investigate the involvement of migrasomes, novel intercellular communication organelles, in the carcinogenesis of OLK. Migrasomes were observed through electron microscopy and multiplex immunofluorescence in OLK and OSCC tissues, and the purified migrasomes were characterized by wheat germ agglutinin staining, long-term imaging, Western blot, and electron microscopy. Single-cell RNA sequencing analysis was conducted to evaluate the effect of migrasomes on the microenvironment. The combined analysis of the quantitative proteome of migrasomes and the transcriptome of recipient cells was used to investigate the involvement of migrasomes in the carcinogenesis of OLK. Xenograft tumors and a mouse model of tongue leukoplakia helped verify migrasomes’ participation in carcinogenesis. Migrasomes were found in both human OLK and OSCC tissues. Notably, migrasomes isolated from dysplastic oral keratinocyte DOK cells, DOK-transformed cells, and OSCC cell lines exhibited characteristic morphological features and distinct molecular signatures. A significant correlation existed between migrasome score and the infiltration of immune cells. Moreover, the protein cargoes within migrasomes promoted leukoplakia carcinogenesis by inducing an immunosuppressive microenvironment. This study reveals that migrasomes drive leukoplakia carcinogenesis. It not only deepens the understanding of the interaction between dysplastic keratinocytes and immune cells during this process but also provides potential diagnostic biomarkers or targets for the treatment of the precancer stage of OSCC.