Pan-Cancer Analysis of the Developmental Pathways Reveals Non-Canonical Wnt Signaling as a Driver of Mesenchymal-Type Tumors

ABSTRACT The processes of angiogenesis, cell proliferation, invasion, and migration, and the signaling pathways that drive these events, are activated in both cancer and during embryonic development. Here, we systematically assessed how the activity of major developmental signaling pathways, represented by the expression of genes encoding components of the pathways, correlated with patient survival in ∼8000 patients across 17 cancer types. We also compared the expressed genes enriched in developmental pathways with those associated with epithelial-mesenchymal transition (EMT) both in a cancer cohort and in mice during embryonic development. We found that EMT and gene expression profiles consistent with high activity of several developmental pathways, including the TGFβ, Notch, and non-canonical Wnt pathways, significantly correlated with poor patient survival in multiple cancer types. We investigated individual components of these pathways and found that expression of the gene encoding the non-canonical Wnt receptor, frizzled 2 (FZD2), is highly correlated with both poor patient survival and gene expression indicating EMT in the tumors. Further mechanistic studies and pathway analyses revealed that FZD2-regulated genes in cancer cells in culture or FZD2-regulated gene sets from the TCGA data or FZD2-regulated genes involved in mouse organogenesis converged in EMT-associated biological processes, suggesting that FZD2 is a key driver of mesenchymal-like cell state and thus a contributor to cancer progression and metastasis.