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.

Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs

“…The physiological function of nc886 RNAs remains largely unknown, although it has been suggested to function as a tumor-sensing molecule [3], oncogene [15], and tumor suppressor [41]. Notably, cancer initiation and progression are associated with the dysregulation of developmental pathways [48][49][50]. Our results connect nc886 epiallele methylation and RNA expression, for the first time, to metabolic traits in childhood and early adulthood.…”

KiRNet: Kinase-centered network propagation of pharmacological screen results

“…Although none of these data are needed to run KiRNet, incorporating them gives the user better metrics to optimize and assess the models (demonstrated below). We collected previously published data on genetic mutations and RNA expression levels for Huh7 WT and Huh7-Fzd2 cell lines ( Cerami et al, 2012 ; Gao et al, 2013 ; Xue et al, 2020 ). Kinase protein and phosphopeptide expression for Huh7 WT and Huh7-Fzd2 cell lines were determined by using our kinobead and liquid chromatography-mass spectrometry (LC-MS) kinome profiling workflow as described previously (see STAR Methods ) ( Golkowski et al, 2017 , 2020a ).…”

“…We analyzed mRNA expression of the high-value genes across 17 different cancer types in TCGA database ( The Cancer Genome Atlas Research Network, 2017 ). Samples in TCGA were stratified into epithelial- or mesenchymal-like cell states based on the expression of key marker genes, as defined previously ( Xue et al, 2020 ) (see STAR Methods ). A high-value signature was computed for each sample from expression levels of the 166 high-value genes.…”

“…Both cell lines were grown at 37°C under 5% CO2, 95% ambient atmosphere and maintained in Dulbecco’s minimum essential medium (DMEM) supplemented with 10% FBS (Sigma) and 1% Penn Strep. Stable cell lines, FOCUS cells with depleted levels of FZD2 and Huh7 cells expressing FZD2 , were generated and cultured as described previously ( Gujral et al, 2014b ; Xue et al, 2020 ).…”

Targeting Wnt Signaling in Endometrial Cancer

“…Wnt/β-catenin pathway activation is a pivotal regulator of epithelial-mesenchymal transition (EMT) [ 51 , 52 , 53 ]. Wnt signaling is associated with increased expression of Snail, Slug and Twist, which control downregulation of the adherens junction protein epithelial (E)-cadherin and upregulation of mesenchymal specific marker neuronal (N)-cadherin during EMT, promoting cell migration.…”