Revealing Molecular Mechanisms of Early-Onset Tongue Cancer by Spatial Transcriptomics

Abstract

Tongue cancer at a young age demonstrates an increase in incidence, aggressiveness, and poor response to therapy. Classic etiological factors for head and neck tumors such as tobacco, alcohol, and human papillomavirus are not related to early-onset tongue cancer. Mechanisms of development and progression of this cancer remain unclear. In this study, we performed spatial whole-transcriptome profiling of tongue cancer in young adults compared with elderly patients. Oxidative stress, vascular mimicry, and MAPK and JAK-STAT pathways were enriched in early-onset tongue cancer. Tumor microenvironment demonstrated increased gene signatures corresponding to myeloid-derived suppressor cells, tumor-associated macrophages, and plasma cells. The invasive front was accompanied by vascular mimicry with arrangement of tumor-associated macrophages and aggregations of plasma cells and lymphocytes organized into tertiary lymphoid structures. Taken together, these results indicate that early-onset tongue cancer has distinct spatial transcriptomic features and molecular mechanisms compared to older patients. HIGHLIGHTSO_LIEarly-onset tongue cancer demonstrates extremely downregulated oxidative phosphorylation and upregulated glycolysis. C_LIO_LIMAPK pathway is the key player in the pathogenesis of tongue cancer in young adults. C_LIO_LIEarly-onset tongue cancer is characterized by JAK-STAT dependent vascular mimicry supported by tumor-associated macrophages at the invasive edge. C_LIO_LITongue cancer microenvironment in young adults enriches for immunosuppressive myeloid derived suppressor cells and demonstrates reduced antigen presentation function. C_LIO_LIThe tumor border in early-onset tongue cancer is enriched with plasma cells and lymphocytes in tertiary lymphoid structures. C_LI