The deadly cross-talk between Hippo pathway and epithelial–mesenchymal transition (EMT) in cancer

Ακρίδα, Ιωάννα; Bravou, Vasiliki; Papadaki, Helen

doi:10.1007/s11033-022-07590-z

Cited by 40 publications

(32 citation statements)

References 90 publications

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“…Recent studies have provided insights into the molecular mechanisms underlying sustained EMT in CSC [ 46 ]. Interestingly, SNAIL contributes to several signaling pathways in EMT regulation, including those that involve STAT3 [ 47 ] and the Hippo pathway [ 48 ]. The regulation of EMT by SNAIL is also centered by several other signaling pathways, including primary mediators TGFβ, Notch, Wnt, TNFα, Hedgehog, and RTKs [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

A Signaling Crosstalk Links SNAIL to the 37/67 kDa Laminin-1 Receptor Ribosomal Protein SA and Regulates the Acquisition of a Cancer Stem Cell Molecular Signature in U87 Glioblastoma Neurospheres

Gresseau

Roy

Duhamel

et al. 2022

Cancers

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Background: Three-dimensional in vitro neurospheres cultures recapitulate stemness features associated with poor clinical outcome in glioblastoma patients. They are commonly used to address brain cancer stem cell (CSC) signal transducing biology that regulates spheroids formation and stemness phenotype, and to assess the in vitro pharmacological impact of chemotherapeutic drugs. Objective: Here, we addressed the role of a new signaling axis involved in the regulation of in vitro spheroids formation and assessed the chemopreventive ability of diet-derived epigallocatechin gallate (EGCG) to impact the processes that govern the acquisition of spheroids CSC stemness traits. Methods: Neurospheres were generated from adherent human U87 glioblastoma cancer cell cultures under conditions that recapitulate stemness features. Total RNA and protein lysates were isolated for gene expression by RT-qPCR and protein expression by immunoblot. Transcriptomic analysis was performed through RNA-Seq. Results: Compared to their parental adherent cells, tumorspheres expressed increased levels of the CSC markers NANOG, SOX2, PROM1 (CD133), as well as of the epithelial-to-mesenchymal transition (EMT) markers Fibronectin, SNAI1, and 37/67 kDa laminin-1 receptor ribosomal protein SA (RPSA). Increased PROM1, SOX2, Fibronectin, and RPSA transcripts level were also observed in clinical grade IV glioblastoma tissues compared to normal tissue. EGCG treatment reduced dose-dependently tumorspheres size and inhibited the transcriptional regulation of those genes. An apoptotic signature was also found in spheroids with increased signal transducing events involving GSK3α/β, RSK, and CREB. These were repressed upon RPSA gene silencing and partially by SNAI1 silencing. Conclusion: This work highlights a signaling axis linking RPSA upstream of SNAIL in neurospheres genesis and supports the chemopreventive impact that diet-derived EGCG may exert on the acquisition of CSC traits.

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Section: Discussionmentioning

confidence: 99%

A Signaling Crosstalk Links SNAIL to the 37/67 kDa Laminin-1 Receptor Ribosomal Protein SA and Regulates the Acquisition of a Cancer Stem Cell Molecular Signature in U87 Glioblastoma Neurospheres

Gresseau

Roy

Duhamel

et al. 2022

Cancers

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“…One critical EMT-TF that was highly upregulated in our model was YAP1. This is significant for a couple of reasons: i) as a transcription activator, YAP1 overexpression promotes EMT in multiple cancers (Akrida et al, 2022), and ii) YAP1 enhances chemoresistance in a subpopulation of SCLC (Pearsall et al, 2020;Wu et al, 2021). Nuclear translocation of YAP1 following Hippo pathway inactivation has been extensively studied.…”

Section: Figurementioning

confidence: 99%

“…Moreover, this transcriptome reprogramming was accompanied by significant increase in ZEB1, ZEB2 and TWIST2 EMT-TFs in cancer cells. Importantly, Yes-associated protein (YAP1), a critical component of the Hippo pathway and co-activator of genes related to EMT and cell growth (Akrida et al, 2022), was also highly upregulated in cancer cells upon direct contact with fibroblasts. The cancer cells reprogramming by fibroblasts was transient and upon separation from fibroblasts cancer cells slowly reverted to their original more epithelial phenotype.…”

Section: Introductionmentioning

confidence: 99%

Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model

Dhungel

Youngblood

Chu

et al. 2023

Front. Mol. Biosci.

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The tumor microenvironment (TME) is the source of important cues that govern epithelial-to-mesenchymal transition (EMT) and facilitate the acquisition of aggressive traits by cancer cells. It is now recognized that EMT is not a binary program, and cancer cells rarely switch to a fully mesenchymal phenotype. Rather, cancer cells exist in multiple hybrid epithelial/mesenchymal (E/M) states responsible for cell population heterogeneity, which is advantageous for the ever-changing environment during tumor development and metastasis. How are these intermediate states generated and maintained is not fully understood. Here, we show that direct interaction between small cell lung carcinoma cells and lung fibroblasts induces a hybrid EMT phenotype in cancer cells in which several mesenchymal genes involved in receptor interaction with the extracellular matrix (ECM) and ECM remodeling are upregulated while epithelial genes such as E-cadherin remain unchanged or slightly increase. We also demonstrate that several core EMT-regulating transcription factors (EMT-TFs) are upregulated in cancer cells during direct contact with fibroblasts, as is Yes-associated protein (YAP1), a major regulator of the Hippo pathway. Further, we show that these changes are transient and reverse to the initial state once the interaction is disrupted. Altogether, our results provide evidence that tumor cells’ direct contact with the fibroblasts in the TME initiates a signaling cascade responsible for hybrid E/M states of cancer cells. These hybrid states are maintained during the interaction and possibly contribute to therapy resistance and immune evasion, while interference with direct contact will result in slow recovery and switch to the initial states.

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“…Zhong et al found that MIAT induces the process of EMT via Wnt/β-catenin signaling pathway in tongue squamous cell carcinoma 24 . It is known that Hippo pathway-mediated EMT process is involved in cancers 25 . Huang et al found that PDLIM1 knockdown-mediated EMT process contributes to YAP up-regulation in HCC 26 .…”

Section: Discussionmentioning

confidence: 99%

LncRNA-MIAT activates hepatic stellate cells via regulating Hippo pathway and epithelial-to-mesenchymal transition

et al. 2023

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Long non-coding RNA-myocardial infarction-associated transcript (lncRNA-MIAT) has been reported to play an important role in the development of multiple cancers. However, the biological roles of MIAT in liver fibrosis are still unknown. In this study, the expression of MIAT is up-regulated during liver fibrosis. Silencing MIAT leads to the suppression of hepatic stellate cell (HSC) proliferation and collagen expression. Double immunofluorescence analysis additionally demonstrates that MIAT inhibition leads to the suppression of type I collagen and α-SMA in vitro. In vivo, MIAT knockdown contributes to the inhibition of fibrosis progression and collagen accumulation. MIAT is confirmed as a target of miR-3085-5p, and the co-location of MIAT and miR-3085-5p is found in HSC cytoplasm. Interestingly, there is a negative correlation between MIAT expression and miR-3085-5p level in cirrhotic patients as well as activated HSCs. In addition, the effects of MIAT inhibition on HSC inactivation are blocked down by miR-3085-5p inhibitor. YAP is a target of miR-3085-5p. Reduced YAP caused by loss of MIAT is reversed by miR-3085-5p inhibitor. Notably, YAP knockdown results in the suppression of MIAT-mediated epithelial-to-mesenchymal transition (EMT) process. In conclusion, we demonstrate that MIAT enhances the activation of HSCs, at least in part, via miR-3085-5p/YAP/EMT signaling pathway.

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The deadly cross-talk between Hippo pathway and epithelial–mesenchymal transition (EMT) in cancer

Cited by 40 publications

References 90 publications

A Signaling Crosstalk Links SNAIL to the 37/67 kDa Laminin-1 Receptor Ribosomal Protein SA and Regulates the Acquisition of a Cancer Stem Cell Molecular Signature in U87 Glioblastoma Neurospheres

A Signaling Crosstalk Links SNAIL to the 37/67 kDa Laminin-1 Receptor Ribosomal Protein SA and Regulates the Acquisition of a Cancer Stem Cell Molecular Signature in U87 Glioblastoma Neurospheres

Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model

LncRNA-MIAT activates hepatic stellate cells via regulating Hippo pathway and epithelial-to-mesenchymal transition

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