Fig. 5

Proposed model of the primary cause of LNM in HNC: In normal squamous epithelial cells, p53 induces cell cycle arrest by indirectly repressing cell cycle genes, via the p53-DREAM pathway [85]. Specifically, the p53-DREAM pathway represses transcription of G1/S and G2/M phase cell cycle genes [60], such as those within cluster L4, the most significant subset of pro-LNM genes that was identified in this study. Abrogation of the p53-DREAM pathway due to either TP53 mutations or HPV [93] causes overexpression of cluster L4 genes as an early tumorigenic event (prior to malignant transformation), resulting in cellular proliferation. Upregulation of cluster L4 genes appears to cause epithelial differentiation, which is associated with epithelial dysplasia in premalignant lesions, dedifferentiation in HNC populations, and stemness within malignant cells. Dedifferentiation could be caused by upregulation of cell cycle genes, resulting in a switch from a differentiated to a proliferative state [101, 102]. Dedifferentiation could be also be induced by overexpression of genes in cluster L4 that encode stemness-related epigenetic modifying enzymes such as DNMT1 [118] and SUZ12 [119], or other stemness drivers such as BIRC5 [120] and RFC4 [121]. Our findings suggest that dedifferentiation promotes LNM by giving rise to cancer stem-like cells that have increased potential to seed metastasis [122]