A Transcriptional Program for Detecting TGFβ-Induced EMT in Cancer.

Momeneh Foroutan,Joseph Cursons,Melissa J. Davis,Soroor Hediyeh-Zadeh,Erik W. Thompson

doi:10.1158/1541-7786.mcr-16-0313

Abstract

Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGFβ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGFβ-induced EMT which can be used to score TGFβ-driven EMT in cells and clinical specimens. Considering this signature in pan-cancer cell and tumor datasets, a number of cell lines (including basal B breast cancer and cancers of the central nervous system) show evidence for TGFβ-driven EMT and carry a low mutational burden across the TGFβ signaling pathway. Furthermore, significant variation is observed in the response of high scoring cell lines to some common cancer drugs. Finally, this signature was applied to pan-cancer data from The Cancer Genome Atlas to identify tumor types with evidence of TGFβ-induced EMT. Tumor types with high scores showed significantly lower survival rates than those with low scores and also carry a lower mutational burden in the TGFβ pathway. The current transcriptomic signature demonstrates reproducible results across independent cell line and cancer datasets and identifies samples with strong mesenchymal phenotypes likely to be driven by TGFβ.Implications: The TGFβ-induced EMT signature may be useful to identify patients with mesenchymal-like tumors who could benefit from targeted therapeutics to inhibit promesenchymal TGFβ signaling and disrupt the metastatic cascade. Mol Cancer Res; 15(5); 619-31. ©2017 AACR.

Highlights

Epithelial-to-mesenchymal transition (EMT) is a physiologic process involved in development (1) and wound healing (2) subverted during cancer metastasis, together with the reverse MET process (3)
Six differentially expressed genes (DEG) were shared across all studies (COL1A1, FN1, ADAM19, SERPINE1, TAGLN, and PMEPA1), all of which are associated with EMT and TGFb stimulation
The association our TGFb–EMT scores (TES) shows with epithelial and mesenchymal scores suggests that TGFb signaling contributes to EMT in numerous cancer cell lines (Fig. 3C–G) and tumors (Fig. 5B–D); there are interesting discrepancies

Summary

Introduction

Epithelial-to-mesenchymal transition (EMT) is a physiologic process involved in development (1) and wound healing (2) subverted during cancer metastasis, together with the reverse MET process (3). EMT is associated with a migratory, invasive phenotype and cancer stem cell (CSC) characteristics that aid metastasis, promote drug resistance, and repress apoptosis (4). Suggests that EMT is a phenotypic endpoint that can be driven by different stimuli, with important implications for drug responses (8). TGFb is a canonical driver of EMT (9). Mutations in the TGFb pathway can promote cell invasiveness and motility, and reduced TGFb type II receptor (TGFBR2) expression has been reported in different cancer types (10). In various cancer cell lines, active TGFb signaling induces the promesenchymal transcription factors SNAI1 and SNAI2, which in turn suppress expression of E-cadherin (CDH1), resulting in loss of cell–cell junctions (11). TGFb controls important EMT markers through both canonical and noncanonical signaling in different cancers (12). Note that EMT is regulated through transcription and is influenced and maintained through interconnected changes in epigenetics (13), micro-RNAs (14), long, noncoding RNAs (15), and protein synthesis (16, 17)

Methods

Results

Conclusion