EMT
58653886
EMT Transition States during Tumor Progression and Metastasis.
Epithelial mesenchymal transition (EMT) is a process in which epithelial cells acquire mesenchymal features. In cancer, EMT is associated with tumor initiation, invasion, metastasis, and resistance to therapy. Recently, it has been demonstrated that EMT is not a binary process, but occurs through distinct cellular states. Here, we review the recent studies that demonstrate the existence of these different EMT states in cancer and the mechanisms regulating their functions. We discuss the different functional characteristics, such as proliferation, propagation, plasticity, invasion, and metastasis associated with the distinct EMT states. We summarize the role of the transcriptional and epigenetic landscapes, gene regulatory network and their surrounding niche in controlling the transition through the different EMT states.
Trends in cell biology
Ievgenia Pastushenko Cedric Blanpain
57373449
Non redundant functions of EMT transcription factors
Epithelial mesenchymal transition (EMT) is a crucial embryonic programme that is executed by various EMT transcription factors (EMT TFs) and is aberrantly activated in cancer and other diseases. However, the causal role of EMT and EMT TFs in different disease processes, especially cancer and metastasis, continues to be debated. In this Review, we identify and describe specific, non redundant functions of the different EMT TFs and discuss the reasons that may underlie disputes about EMT in cancer.This Review describes non redundant functions of the core transcription factors that mediate the epithelial mesenchymal transition, and discusses the conflicting results regarding their roles in this process.
Nature Cell Biology
Marc P Stemmler Rebecca L Eccles Simone Brabletz Thomas Brabletz
109939612
Context dependent EMT programs in cancer metastasis
In this review, Aiello and Kang discuss the molecular mechanisms, regulatory networks, and functional consequences of epithelial mesenchymal transition (EMT) in the context of cancer metastasis, with a particular focus on partial EMT and cellular plasticity.
The Journal of experimental medicine
Nicole M Aiello Yibin Kang
29947968
EMT in cancer
Similar to embryonic development, changes in cell phenotypes defined as an epithelial to mesenchymal transition (EMT) have been shown to play a role in the tumorigenic process. Although the first description of EMT in cancer was in cell cultures, evidence for its role in vivo is now widely reported but also actively debated. Moreover, current research has exemplified just how complex this phenomenon is in cancer, leaving many exciting, open questions for researchers to answer in the future. With these points in mind, we asked four scientists for their opinions on the role of EMT in cancer and the challenges faced by scientists working in this fast moving field.
Nature Reviews Cancer
Thomas Brabletz Raghu Kalluri M Angela Nieto Robert A Weinberg
4933657
Identification of the tumour transition states occurring during EMT
In cancer, the epithelial to mesenchymal transition (EMT) is associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary process, EMT occurs through distinct intermediate states. However, there is no direct in vivo evidence for this idea. Here we screen a large panel of cell surface markers in skin and mammary primary tumours, and identify the existence of multiple tumour subpopulations associated with different EMT stages: from epithelial to completely mesenchymal states, passing through intermediate hybrid states. Although all EMT subpopulations presented similar tumour propagating cell capacity, they displayed differences in cellular plasticity, invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes identify the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulate EMT transition states.Epithelial to mesenchymal transition in tumour cells occurs through distinct intermediate states, associated with different metastatic potential, cellular properties, gene expression, and chromatin landscape
Nature
Ievgenia Pastushenko Audrey Brisebarre Alejandro Sifrim Marco Fioramonti Tatiana Revenco Soufiane Boumahdi Alexandra Van Keymeulen Daniel Brown Virginie Moers Sophie Lemaire Sarah De Clercq Esmeralda Minguijon Cedric Balsat Youri Sokolow Christine Dubois Florian de Cock Samuel Scozzaro Federico Sopena Angel Lanas Nicky D'Haene Isabelle Salmon Jean-Christophe Marine Thierry Voet Panagiota A Sotiropoulou Cedric Blanpain
4520370
EMT, CSCs, and drug resistance: the mechanistic link and clinical implications
The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity that is, the phenotypic diversity of cancer cells co inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial to mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.
Nature Reviews Clinical Oncology
Tsukasa Shibue Robert A Weinberg
49311081
EMT Subtype Influences Epithelial Plasticity and Mode of Cell Migration.
Epithelial mesenchymal transition (EMT) is strongly implicated in tumor cell invasion and metastasis. EMT is thought to be regulated primarily at the transcriptional level through the repressive activity of EMT transcription factors. However, these classical mechanisms have been parsed out almost exclusively in vitro, leaving questions about the programs driving EMT in physiological contexts. Here, using a lineage labeled mouse model of pancreatic ductal adenocarcinoma to study EMT in vivo, we found that most tumors lose their epithelial phenotype through an alternative program involving protein internalization rather than transcriptional repression, resulting in a "partial EMT" phenotype. Carcinoma cells utilizing this program migrate as clusters, contrasting with the single cell migration pattern associated with traditionally defined EMT mechanisms. Moreover, many breast and colorectal cancer cell lines utilize this alternative program to undergo EMT. Collectively, these results suggest that carcinoma cells have different ways of losing their epithelial program, resulting in distinct modes of invasion and dissemination.
Developmental cell
Nicole M Aiello Ravikanth Maddipati Robert J Norgard David Balli Jinyang Li Salina Yuan Taiji Yamazoe Taylor A Black Amine Sahmoud Emma Elizabeth Furth Dafna Bar-Sagi Ben Z Stanger
13619676
Regulatory networks defining EMT during cancer initiation and progression
Epithelial to mesenchymal transition (EMT) is essential for driving plasticity during development, but is an unintentional behaviour of cells during cancer progression. The EMT associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them. Disturbance of a controlled epithelial balance is triggered by altering several layers of regulation, including the transcriptional and translational machinery, expression of non coding RNAs, alternative splicing and protein stability.
Nature Reviews Cancer
Bram de Craene Geert Berx
24920079
EMT: Mechanisms and therapeutic implications
Abstract Metastasis, the dissemination of cancer cells from primary tumors, represents a major hurdle in the treatment of cancer. The epithelial mesenchymal transition (EMT) has been studied in normal mammalian development for decades, and it has been proposed as a critical mechanism during cancer progression and metastasis. EMT is tightly regulated by several internal and external cues that orchestrate the shifting from an epithelial like phenotype into a mesenchymal phenotype, relying on a delicate balance between these two stages to promote metastatic development. EMT is thought to be induced in a subset of metastatic cancer stem cells (MCSCs) bestowing this population with the ability to spread throughout the body and contributing to therapy resistance. The EMT pathway is of increasing interest as a novel therapeutic avenue in the treatment of cancer, and could be targeted to prevent tumor cell dissemination in early stage patients or to eradicate existing metastatic cells in advanced stages. In this review, we describe the sequence of events and defining mechanisms that take place during EMT, and how these interactions drive cancer cell progression into metastasis. We summarize clinical interventions focused on targeting various aspects of EMT and their contribution to preventing cancer dissemination.
Pharmacology therapeutics
Mohini Singh Nicolas Yelle Chitra Venugopal Sheila K Singh
23749736
The EMT activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer
Metastasis is the major cause of cancer associated death. Partial activation of the epithelial to mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1 cre mediated activation of mutant Kras and p53 (KPC model) the EMT TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT TFs to target these factors simultaneously.
Nature Cell Biology
Angela M Krebs Julia Mitschke Maria Lasierra Losada Otto Schmalhofer Melanie Boerries Hauke Busch Martin Boettcher Dimitrios Mougiakakos Wilfried Reichardt Peter Bronsert Valerie G Brunton Christian Pilarsky Thomas H Winkler Simone Brabletz Marc P Stemmler Thomas Brabletz