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SnapShot The Epithelial-Mesenchymal Transition


SnapShot: The Epithelial-Mesenchymal Transition
JAG2 IL-6 Growth factors NOTCH IL-6R BMPR1 BMPR2 Claudin Occludin Smad2/3
P

1

Jonathan P. Sleeman3,4 and Jean Paul Thiery2,3 IMCB and Experimental Therapeutics Centre, Biopolis A*STAR, 138673 Singapore; 2Cancer Science Institute, 117456 Singapore 3 University of Heidelberg, Medical Faculty Mannheim, D-68167 Mannheim, Germany; 4Karlsruhe Institute of Technology, Postfach 3640, 76021 Karlsruhe, Germany
MESENCHYMAL
Hedgehog
BMPs

EPITHELIAL

Smoothened

Patched

Microtentacles

RTK

Tight junction
Actin
ZO3 ZO1 ZO2 ER STAT3 PI3K Ras

Claudin ZO3 ZO1 ZO2

Par3 Par6

E-cadherin Transcription

p120-Cat Kaiso

p120-Cat

DOI 10.1016/j.cell.2011.03.029
LIV1 MAPK Snail1/2
P

p120-Cat

162 Cell 145, April 1, 2011 ?2011 Elsevier Inc.
Other EMT-inducing pathways ILEI Endothelin-A receptor-PI3K TNF-α-NF-κB, Akt Hyaluronic acid COX2-PGE2 AMF PTH(rP)R Bile acids Nicotine UV irradiation SCF Axl-Gas6
AKT TβRI β TβRI TGF-β TβRII Smurf1 Par6 P Par3 aPKC JAM

Balanced activities

RhoA

Occludin

Cdc42

Stabilized actin cytoskeleton
PAK1
Proteas ome

Rac1
Ub

Par6 TβRI Par3 aPKC JAM

Dissociation of tight junctions

RhoA

DAB2

IQGAP F-actin β-cat -cat
Ub

Adherens junction
P

Focal adhesion formation
Rap1

Other EMT-associated effects Resistance to senescence Resistance to apoptosis Therapy resistance Stemness

Nectin Afadin CSL X β-cat α-cat Vinculin α-Actinin NF-κB AKT GSK3β β-cat c-src
P

ILK CK1E
P

Glu-tubulin

Clip170 EB1 Dynein/ dynactin complex β-cat FAK

E-cadherin

Endocytosis degradation Focal adhesion formation
FAK Hakai

Loss of desmosomes

Ninein

DDR1

Apicobasal microtubules DAP21P miR-200 miR-205 GSK3β

Collective RhoE cell p190 migration
NF-κB Gli1 MTA3

Loss of gap junctions Adherens junction disassembly Cytoskeleton remodeling

Rho GAP

Dishevelled LRP5/6 Cytokeratin Plakoglobin Desmoplakin GSC LoxL2 E2.2 KLF8 E47 p120-Cat FOXQ1 Twist Zeb1/2

RhoA

Frizzled Wnt β-cat α-cat
P

Myosin light chain P

ROCK

Examples of downregulated genes Tubulin tyrosine ligase Claudins Occludins ZO1/ZO3 Crumbs3 Desmoplakin Connexin43 E-cadherin Nectin-1 VE-cadherin Cytokeratins A Collagen I, II

Cdc42 Rac1

Membrane ruf es
N-cad PDGF

Snail1/2

Desmosome

Desmocollin

p53

Desmoglein

c-src RTK

Increased TGF-β signaling
Afadin Nectin

p190 Rho GAP β-cat p120-Cat RhoA PDGFR

miR-200 miR-205

Snail1/2

Zeb1/2

Gap junction
Upregulated genes (see box B)
HIF 1/2

E-cadherin and other downregulated genes (see box A)
Collagen 1

Examples of upregulated genes Six1 TβRI Vimentin SMA N-cadherin NCAM Fibronectin Laminins miR-661 B MMPs
FAK p130 CAS Pyk2 DDR1

FAK
P Fyn

p190 Rho GAP

Rac1 NCAM

E-cadherin degradation
Reactive oxygen species Rac1b MMPs

RhoA

Cdc42

Focal adhesion assembly and turnover Filopodia Lamellipodia Migration Invasion

FOXA1/2

BASEMENT MEMBRANE

Integrin α6β4 Laminin 5

Plectin

Hypoxia

ECM remodelling

See online version for legend and references.

Basement membrane degradation

SnapShot: The Epithelial-Mesenchymal Transition
1

Jonathan P. Sleeman3,4 and Jean Paul Thiery1,2 IMCB and Experimental Therapeutics Centre, Biopolis A*STAR, 138673 Singapore 2 Cancer Science Institute, 117456 Singapore 3 University of Heidelberg, Medical Faculty Mannheim, D-68167 Mannheim, Germany 4 Karlsruhe Institute of Technology, Postfach 3640, 76021 Karlsruhe, Germany
This SnapShot portrays important regulatory pathways and major cellular events that are activated during the transition from an epithelial to a mesenchymal morphology during development and disease. The cell on the left represents the epithelial state, whereas the central cell depicts transcriptional regulatory networks that orchestrate the process of epithelial-to-mesenchymal transition (EMT). The cell on the right illustrates some of the consequences of the activity of these networks that endow formerly epithelial cells with mesenchymal characteristics. Note that this overview does not take into account cell-type-specific regulation of EMT, and that not all illustrated mechanisms are obligate for EMT to occur. The temporal regulation of the EMT process is also not considered in this SnapShot. The Epithelial Phenotype Polarized epithelial cells are typified by tight junctions, adherens junctions, desmosomes, and gap junctions. Junctional complexes not only act as mediators of polarized cell-cell contacts but also serve as anchor points for the actin cytoskeleton. Adherens junctions can additionally anchor apicobasal microtubule arrays, and through E-cadherin-DDR1 interactions are also involved in collective cell migration. Organization of the actin cytoskeleton, microtubule arrays, and cell-cell junctions is tightly coordinated in a mechanism that probably involves IQGAP, but the details remain to be investigated. Balanced regulation of the activities of RhoA (stress fibers), Cdc42 (filopodia), and Rac1 (lamellipodia) stabilizes the actin cytoskeleton and maintains the epithelial phenotype. Epithelial cells are tethered to the underlying basement membrane, for example through integrins. The repression of EMT-inducing transcriptional regulators (for example, through microRNAs), as well the activity of positively acting factors such as FOXA1/2, ensures that expression of key junctional proteins such as E-cadherin is maintained. Suppression of GSK3β also helps to maintain the epithelial phenotype. Transcriptional Activation of EMT A variety of extracellular stimuli have the potential to induce EMT. A complex network of positively and negatively acting signal transduction mechanisms converge on the nucleus to downregulate genes required for the epithelial phenotype and to upregulate genes that specify mesenchymal characteristics. GSK3β and NF-κB play central roles in coordinating these pathways. Members of the Snail family of transcriptional regulators, namely Snail1 and Snail2, have emerged as a key regulatory node. The zinc finger transcription factors Zeb1 and Zeb2 also make a pivotal contribution to this regulation. EMT-inducing signals promote their expression, regulate their stability, and/or alter their subcellular location. Loss of Epithelial and Acquisition of Mesenchymal Characteristics Key targets of the pathways that induce EMT include the adherens junction components E-cadherin and β-catenin. In addition to being transcriptionally downregulated and epigenetically switched off, E-cadherin can be proteolytically cleaved and targeted to endosomes for degradation. Proteosomal degradation of β-catenin destabilizes adherens junctions, whereas loss of E-cadherin can increase the free pool of β-catenin that can then enter the nucleus and modulate transcription. An important consequence of EMTinducing transcriptional modulation as well as other pro-EMT processes is the loss of the junctional complexes that typify polarized epithelial cells. Enhanced activation of the GTPases Cdc42 and Rac1 and suppression of RhoA favor the formation of lamellipodia and filopodia, migration, and invasion. A variety of mechanisms promote the assembly and turnover of focal adhesions. Extensive cytoskeleton remodeling occurs, including switching from a predominantly cytokeratin to a vimentin-rich intermediate filament network. Detyrosination of tubulin promotes microtentacle formation. Proteolytic enzymes are produced that together with increased expression of extracellular matrix components serve to remodel the microenvironment surrounding the cells. Other properties endowed on cells undergoing EMT include resistance to apoptosis, senescence, and therapeutics and the acquisition of stemness characteristics. Acknowledgments This work was supported by a grant to J.P.S. from the European Union under the auspices of the FP7 collaborative project TuMIC, contract no. HEALTH-F2-2008-201662. RefeRences Casas, E., Kim, J., Bendesky, A., Ohno-Machado, L., Wolfe, C.J., and Yang, J. (2011). Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res. 71, 245–254. Chang, C.J., Chao, C.H., Xia, W., Yang, J.Y., Xiong, Y., Li, C.W., Yu, W.H., Rehman, S.K., Hsu, J.L., Lee, H.H., et al. (2011). p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol. 13, 317–323. Hanahan, D., and Weinberg, R.A. (2011). Hallmark of cancers: the next generation. Cell 144, 646–674. Hidalgo-Carcedo, C., Hooper, S., Chaudhry, S.I., Williamson, P., Harrington, K., Leitinger, B., and Sahai, E. (2011). Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat. Cell Biol. 13, 49–58. Peinado, H., Olmeda, D., and Cano, A. (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415–428. Schmalhofer, O., Brabletz, S., and Brabletz, T. (2009). E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 28, 151–166. Thiery, J.P., and Sleeman, J.P. (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7, 131–142. Thiery, J.P., Acloque, H., Huang, R.Y., and Nieto, M.A. (2009). Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890. Whipple, R.A., Matrone, M.A., Cho, E.H., Balzer, E.M., Vitolo, M.I., Yoon, J.R., Ioffe, O.B., Tuttle, K.C., Yang, J., and Martin, S.S. (2010). Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement. Cancer Res. 70, 8127–8137. Yilmaz, M., and Christofori, G. (2009). EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28, 15-33.

162.e1

Cell 145, April 1, 2011 ?2011 Elsevier Inc. DOI 10.1016/j.cell.2011.03.029


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