Integrative Multiomics Analysis of the Angiogenesis-EMT Interface in Head and Neck Squamous Cell Carcinoma

Angiogenesis and epithelial-mesenchymal transition (EMT) are key hallmarks that contribute to the progression of oral squamous cell carcinoma (OSCC), but whether the two programs vary simultaneously across tumors and how much of this reflects tumor composition remain unclear. We scored predefined, non-overlapping 20-gene angiogenesis and EMT signatures with a rank-based method in 342 primary oral cavity tumors from The Cancer Genome Atlas (TCGA-OSCC). The two programs were strongly correlated (Spearman rho = 0.809, P = 2.7 x 10^-80), and 2,396 bridge genes were associated with both programs across the transcriptome. The bridge genes were enriched in pathways associated with focal adhesion and extracellular matrix-receptor interaction. In the cellular case, fibroblast and endothelial marker scores were prominent and correlated with the program scores. The coupling was attenuated but remained positive after joint adjustment for tumor purity and stromal and immune scores (partial rho = 0.406) and with an epithelial-restricted EMT score (rho = 0.710). Further correlation was performed with a partial EMT (pEMT), which shows a significant positive correlation (rho = 0.59) and an inverse correlation with tumor purity (rho = -0.70). 146 final gene candidates were found using multi-omic evidence and candidate-level testing on the external cohort GSE30784; after adjusting for inferred cell fractions, 101 of these candidates supported the dual program. For thorough characterization, three candidates with an emphasis on OSMR, MICAL2, and LHFPL2 were chosen. Additional CPTAC data were used to confirm protein-level support, which was strongest for MICAL2. No significant connection was seen between the Interface score and overall survival (hazard ratio per 1-SD increase, 0.92; 95% CI, 0.78-1.08). These results describe a coordinated angiogenesis-EMT transcriptional state in OSCC that is attenuated but retained after accounting for tumor composition, and nominate candidate genes for experimental study.