Involvement of partial EMT in cancer progression

Saitoh, Masao

doi:10.1093/jb/mvy047

Cited by 385 publications

(308 citation statements)

References 56 publications

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“…Recent research supports the premise that partial EMT, in which cells display both epithelial and mesenchymal traits simultaneously, may be relevant to cancer metastasis (24-26), suggesting that further research into the specific biochemical mechanisms of this partial EMT phenotype are necessary. Our finding that several EMT TFs are sequestered into a single complex, the EMTosome, and the occupancy of DNA binding sites by one member impacts the DNA binding ability/affinity of the other complex members, may offer a mechanistic explanation for the partial EMT state phenotype.…”

Section: Discussionmentioning

confidence: 83%

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site

McCracken

2020

Preprint

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Epithelial-Mesenchymal transition (EMT) of primary tumor cells is a critical trans-differentiation event that contributes to dissemination and metastasis. The process of EMT is controlled by specific DNA-binding transcription factors (TFs) that reprogram the tumor transcriptome. In particular, the canonical EMT-TFs Twist and Snail can induce an EMT program when overexpressed in cancer cells, and both are found upregulated in metastatic cancers. Twist and Snail bind DNA directly, by recognition to variants of the E-Box sequence CANNTG. However, it is unclear how this binding is regulated. We have used a biochemical approach to dissect DNA binding and protein-protein interactions that occur amongst these proteins. We find that Twist preferentially recognizes a dyad repeat of E-boxes that are not directly bound by Snail. Our data suggest that Twist use its WR domain to recruit Snail into a binding complex through the Snail zinc-finger motifs. We analyzed Twist-Snail complexes in the breast carcinoma cell line SUM1315 and found evidence that it contains an additional protein partner, Sox9. Notably, we report that a native Twist complex can be displaced from its dyad binding site by consensus DNA binding sites for Snail and Sox9 even though these proteins do not contact the Twist dyad site. Taken together, our findings suggest that Snail and Sox9 interact with Twist to regulate its DNA binding ability via protein-protein interactions, thereby allosterically regulating Twist DNA binding. We designate this ternary complex EMTosome. These results may inform efforts to therapeutically target the EMT program in order to target cancer metastasis.

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Section: Discussionmentioning

confidence: 83%

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site

McCracken

2020

Preprint

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“…3F , both the TGF-β treatment and drug resistance conferred significant invasive advantage on the MCF7 and MDA-MB-468 cells, rendering them more motile than their parent counterparts, as seen by the increased number of crystal violet-stained migrated cells. Indeed, recent studies have revealed that the partial or hybrid E-M phenotype is attributed to the tumor cell plasticity and is extremely favorable for metastatic dissemination (Kroger et al, 2019, Saitoh, 2018).…”

Section: Resultsmentioning

confidence: 99%

Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells

Vaidya

Wang

Qian

et al. 2019

Preprint

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invasiveness 28 Abbreviations 29 BCa -Breast cancer 30 EDB-FN -Extradomain-B fibronectin 31 FN1 -Fibronectin 32 MRI -Magnetic resonance imaging 33 PET -Positron-emission tomography 34 CT -Computed tomography 35 TME -Tumor microenvironment 36 ECM -Extracellular matrix 37 TGF-β -Transforming growth factor-β 38 EMT -Epithelial to mesenchymal transition 39 CEA -Carcinoembryonic antigen 40 41 42 43 44 45 46 47 48 49 50 51 Summary Statement 52 Dynamic changes in invasive properties of breast cancer cells directly influence extradomain-B 53 fibronectin levels, suggesting its potential role as a molecular marker for active surveillance and 54 therapeutic monitoring of breast cancer. 55 Abstract 56Breast tumor heterogeneity is a major impediment to oncotherapy. Tumor cells undergo rapid 57 clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of 58 specific markers of these high-risk tumors precludes efficient therapeutic and diagnostic 59 management of breast cancer. Given the critical function of tumor microenvironment in the 60 oncogenic circuitry, we sought to determine the role of the extracellular matrix oncoprotein, 61 extradomain-B fibronectin (EDB-FN), as a molecular marker of aggressive cancers. High-risk 62 invasive cell lines generated from relatively less invasive MCF7 and MDA-MB-468 breast cancer 63 cells by long-term TGF-β treatment and chemoresistance demonstrated hybrid epithelial-64 mesenchymal phenotype, enhanced motility, and significantly elevated EDB-FN levels in 2D-and 65 3D-cultures. To determine if EDB-FN could serve as a therapy-predictive marker, the invasive cell 66 lines were treated with MK2206-HCl, a pan-AKT inhibitor. Phospho-AKT depletion reduced 67 EMT and invasion of the populations, with a concomitant decrease in EDB-FN expression, partly 68 through the phosphoAKT-SRp55 pathway, demonstrating that EDB-FN expression is strongly 69 associated with high-risk breast cancer. EDB-FN is a promising molecular marker for accurate 70 detection, differential diagnosis, and non-invasive therapeutic surveillance of aggressive breast 71 cancer. 72 73 74 75 76 77 78 79Breast cancer (BCa) is a devastating disease that accounts for 41,000 deaths each year in 80 the US (Siegel et al., 2018). Although the survival rate for patients with localized BCa is close to 81 99%, it declines precipitously in patients with distant metastases and drug resistance (Siegel et al., 82 2018, DeSantis et al., 2017). A major stumbling block in the clinical management of the disease 83 is tumor heterogeneity, which plays a role in the dynamic nature of BCa progression (Baird and 84 Caldas, 2013). Whole genome sequencing and profiling studies have demonstrated that breast 85 tumors of the same histological subtype exhibit distinct molecular portraits and discrete trajectories 86 in individual BCa patients at different stages (Tsang and Tse, 2019, Eliyatkin et al., 2015, Baird 87 and Caldas, 2013). Stochastic mutations, genome instability, and clonal evolution arising from 88 selective pre...

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“…During EMT, dissolution of adherence junction proteins and disruption of the tight junctions lead the cells to lose their cell‐cell adhesion and apical‐basal polarity, and thus, they become migratory and invasive. However, sometimes it is not easy to divide cancer cells into cells with only epithelial or mesenchymal features, and cells with both epithelial and mesenchymal phenotypes have recently been reported, which is termed partial EMT . Although the phenotypes of NMuMG‐GPNMB(ΔKLD) are different from those of complete EMT and partial EMT, it might be a kind of intermediate phenotype between epithelial and mesenchymal, resulting in fewer migratory and tumorigenic abilities.…”

Section: Discussionmentioning

confidence: 99%

“…However, sometimes it is not easy to divide cancer cells into cells with only epithelial or mesenchymal features, and cells with both epithelial and mesenchymal phenotypes have recently been reported, which is termed partial EMT. 28,29 Although the phenotypes of NMuMG-GPNMB(ΔKLD) are different from those of complete F I G U R E 5 Deletion of the kringle-like domain (KLD) maintains the glycoprotein NMB (GPNMB) function to suppress E-cadherin expression but impairs its function to activate cellular migration and Wnt/β-catenin signaling. A,B, Expressions of GPNMB, E-cadherin, and β-actin in NMuMG-mock, NMuMG-GPNMB(WT) (G3 and G8), and GPNMB(ΔKLD) (∆K7 and ∆K11) cells were examined by RT-PCR for mRNA (A) and by immunoblot analysis for proteins (B).…”

Section: Discussionmentioning

confidence: 99%

Role of the kringle‐like domain in glycoprotein NMB for its tumorigenic potential

et al. 2019

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Glycoprotein NMB (GPNMB) is highly expressed in many types of malignant tumors and thought to be a poor prognostic factor in those cancers, including breast cancer. Glycoprotein NMB is a type IA transmembrane protein that has a long extracellular domain (ECD) and a short intracellular domain (ICD). In general, the ECD of a protein is involved in protein‐protein or protein‐carbohydrate interactions, whereas the ICD is important for intracellular signaling. We previously reported that GPNMB contributes to the initiation and malignant progression of breast cancer through the hemi‐immunoreceptor tyrosine‐based activation motif (hemITAM) in its ICD. Furthermore, we showed that the tyrosine residue in hemITAM is involved in induction of the stem‐like properties of breast cancer cells. However, the contribution of the ECD to its tumorigenic function has yet to be fully elucidated. In this study, we focused on the region, the so‐called kringle‐like domain (KLD), that is conserved among species, and made a deletion mutant, GPNMB(ΔKLD). Enhanced expression of WT GPNMB induced sphere and tumor formation in breast epithelial cells; in contrast, GPNMB(ΔKLD) lacked these activities without affecting its molecular properties, such as subcellular localization, Src‐induced tyrosine phosphorylation at least in overexpression experiments, and homo‐oligomerization. Additionally, GPNMB(ΔKLD) lost its cell migration promoting activity, even though it reduced E‐cadherin expression. Although the interaction partner binding to KLD has not yet been identified, we found that the KLD of GPNMB plays an important role in its tumorigenic potential.

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Involvement of partial EMT in cancer progression

Cited by 385 publications

References 56 publications

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site

Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells

Role of the kringle‐like domain in glycoprotein NMB for its tumorigenic potential

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