Canonical BMP Signaling Executes Epithelial-Mesenchymal Transition Downstream of SNAIL1.

Patrick Frey,Andreas Hecht,Monika Schrempp,Antoine Devisme,Melanie Boerries,Geoffroy Andrieux

doi:10.3390/cancers12041019

Abstract

Epithelial-mesenchymal transition (EMT) is a pivotal process in development and disease. In carcinogenesis, various signaling pathways are known to trigger EMT by inducing the expression of EMT transcription factors (EMT-TFs) like SNAIL1, ultimately promoting invasion, metastasis and chemoresistance. However, how EMT is executed downstream of EMT-TFs is incompletely understood. Here, using human colorectal cancer (CRC) and mammary cell line models of EMT, we demonstrate that SNAIL1 critically relies on bone morphogenetic protein (BMP) signaling for EMT execution. This activity requires the transcription factor SMAD4 common to BMP/TGFβ pathways, but is TGFβ signaling-independent. Further, we define a signature of BMP-dependent genes in the EMT-transcriptome, which orchestrate EMT-induced invasiveness, and are found to be regulated in human CRC transcriptomes and in developmental EMT processes. Collectively, our findings substantially augment the knowledge of mechanistic routes whereby EMT can be effectuated, which is relevant for the conceptual understanding and therapeutic targeting of EMT processes.

Highlights

Epithelial-mesenchymal transition (EMT) is a conserved cellular program with fundamental roles in development, physiology, and various forms of disease
In order to identify pathways and factors operating in EMT execution, we analyzed time-resolved transcriptome data derived from this and factors operating in EMT execution, we analyzed time-resolved transcriptome data derived from model [21]
Gene set enrichment analysis (GSEA) based on Consensus and GO-term databases that several gene sets related to TGFβ superfamily signaling, including bone morphogenetic protein (BMP) signaling, are significantly revealed that several gene sets related to TGFβ superfamily signaling, including BMP signaling, are enriched in the Snail1-HA-inducible transcriptome (Figure 1d)

Summary

Introduction

Epithelial-mesenchymal transition (EMT) is a conserved cellular program with fundamental roles in development, physiology, and various forms of disease. EMT typically entails the gain of motility and invasiveness at the expense of apico-basal polarity and cell–cell adhesion These cellular alterations are manifestations of massive gene expression changes, which can be triggered by a variety of extracellular signals. A central event seemingly common to all conditions that elicit EMT, is the upregulation of a group of master regulators, the so-called EMT-transcription factors (EMT-TFs), most notably comprising SNAIL, ZEB and TWIST family proteins [5,6] These master regulators in turn orchestrate the EMT process by initiating the up- and downregulation of large cohorts of genes specifying mesenchymal and epithelial cell states, respectively [4,7]. Recent studies have hinted that EMT implementation in different settings involves considerable mechanistic diversity [7,8], highlighting the need to further investigate how EMT can be brought about

Methods

Results

Conclusion