Multimodal profiling of oral squamous cell carcinoma identifies genomic alterations and expression programs associated with betel quid chewing [spatial transcriptomics]

To decipher contributory genomic abnormalities and transcriptional reprogramming in these malignancies, we conducted a multi-omics survey, including exome sequencing of tumor-normal pairs, alone with integrated single-cell and spatial transcriptomics of a set of tumors. In addition to enrichment of significantly altered genes (e.g mutations of TP53 and CHUK, copy gains of MAP3K13 and FADD, copy losses of CDKN2A) and mutational signatures associated with BQ chewing, we demonstrated frequently altered oncogenic pathways (Hippo and p53 signaling) and potential combination therapy opportunities linked to BQ use.

Moreover, a shift of tumor microenvironment in BQ-related OSCC, characterized by extensive cell-cell crosstalk and induced tissue hypoxia, dendritic immunosuppression, and endothelial sprouting, was observed. Collectively, these differences in genomic landscape and tumor niche suggest that BQ-positive OSCC could be an etiological subtype different from their BQ-negative counterparts.