Frey Patrick, Devisme Antoine, Schrempp Monika, Andrieux Geoffroy, Boerries Melanie, Hecht Andreas
Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany.
Cancers (Basel). 2020 Apr 21;12(4):1019. doi: 10.3390/cancers12041019.
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.
上皮-间质转化（EMT）是发育和疾病中的一个关键过程。在癌症发生过程中，已知各种信号通路通过诱导SNAIL1等EMT转录因子（EMT-TFs）的表达来触发EMT，最终促进侵袭、转移和化疗耐药性。然而，EMT在EMT-TFs下游如何执行尚未完全了解。在这里，我们使用人类结直肠癌（CRC）和EMT的乳腺细胞系模型，证明SNAIL1在EMT执行过程中严重依赖骨形态发生蛋白（BMP）信号。这种活性需要BMP/TGFβ途径共有的转录因子SMAD4，但与TGFβ信号无关。此外，我们在EMT转录组中定义了一组BMP依赖性基因，这些基因协调EMT诱导的侵袭性，并在人类CRC转录组和发育性EMT过程中受到调控。总体而言，我们的发现极大地增加了对EMT实现机制途径的认识，这与EMT过程的概念理解和治疗靶向相关。
