scholarly journals Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009708
Author(s):  
Brady G. Strittmatter ◽  
Travis J. Jerde ◽  
Peter C. Hollenhorst
Keyword(s):  
Cell Fate ◽  
Transcriptional Activation ◽  
Epithelial To Mesenchymal Transition ◽  
Clonogenic Survival ◽  
Activation Function ◽  
Tumor Formation ◽  
Cell Fates ◽  
Normal Prostate ◽  
Mesenchymal Transition ◽  
Prostate Cells

The TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function.

scholarly journals CENP-A overexpression drives distinct cell fates depending on p53 status

2020 ◽  
Author(s):  
Daniel Jeffery ◽  
Katrina Podsypanina ◽  
Alberto Gatto ◽  
Rebeca Ponce Landete ◽  
Lorraine Bonneville ◽  
...  
Keyword(s):  
Cell Fate ◽  
Epithelial Mesenchymal Transition ◽  
Clonogenic Survival ◽  
Response To Therapy ◽  
Epigenetic Mark ◽  
Cell Fates ◽  
Mesenchymal Transition ◽  
Distinct Cell ◽  
Histone H3 Variant ◽  
P53 Status

AbstractTumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays and single-cell RNA-sequencing over time, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. But, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential precursor for tumour cell invasion and metastasis. Thus, CENP-A overexpression drives distinct cell fates depending on p53 status, with important implications for tumour evolution.

scholarly journals CENP-A overexpression promotes distinct fates in human cells, depending on p53 status

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Daniel Jeffery ◽  
Alberto Gatto ◽  
Katrina Podsypanina ◽  
Charlène Renaud-Pageot ◽  
Rebeca Ponce Landete ◽  
...  
Keyword(s):  
Cell Fate ◽  
Epithelial Mesenchymal Transition ◽  
Clonogenic Survival ◽  
Response To Therapy ◽  
Epigenetic Mark ◽  
Mammalian Development ◽  
Mesenchymal Transition ◽  
Histone H3 Variant ◽  
Tumour Cell Invasion ◽  
P53 Status

AbstractTumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays, single-cell RNA-sequencing and cell trajectory analysis, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. Surprisingly, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential process in mammalian development but also a precursor for tumour cell invasion and metastasis. Thus, we uncover an unanticipated function of CENP-A overexpression to promote cell fate reprogramming, with important implications for development and tumour evolution.

scholarly journals Cytoplasmic NOTCH and membrane-derived β-catenin link cell fate choice to epithelial-mesenchymal transition during myogenesis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Daniel Sieiro ◽  
Anne C Rios ◽  
Claire E Hirst ◽  
Christophe Marcelle
Keyword(s):  
Cell Fate ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Epithelial Plasticity ◽  
Cellular Environment ◽  
Muscle Formation ◽  
Fate Decision ◽  
Gsk 3Β ◽  
Coupling Cell

How cells in the embryo coordinate epithelial plasticity with cell fate decision in a fast changing cellular environment is largely unknown. In chick embryos, skeletal muscle formation is initiated by migrating Delta1-expressing neural crest cells that trigger NOTCH signaling and myogenesis in selected epithelial somite progenitor cells, which rapidly translocate into the nascent muscle to differentiate. Here, we uncovered at the heart of this response a signaling module encompassing NOTCH, GSK-3β, SNAI1 and β-catenin. Independent of its transcriptional function, NOTCH profoundly inhibits GSK-3β activity. As a result SNAI1 is stabilized, triggering an epithelial to mesenchymal transition. This allows the recruitment of β-catenin from the membrane, which acts as a transcriptional co-factor to activate myogenesis, independently of WNT ligand. Our results intimately associate the initiation of myogenesis to a change in cell adhesion and may reveal a general principle for coupling cell fate changes to EMT in many developmental and pathological processes.

Dynamic extracellular matrix stiffening induces a phenotypic transformation and a migratory shift in epithelial cells

2020 ◽  
Vol 12 (6) ◽  
pp. 161-174
Author(s):  
Shane C Allen ◽  
Jessica A Widman ◽  
Anisha Datta ◽  
Laura J Suggs
Keyword(s):  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Soft Tissue Tumors ◽  
Tumor Formation ◽  
Matrix Stiffness ◽  
Mesenchymal Transition ◽  
Cell Clusters

Abstract Soft tissue tumors, including breast cancer, become stiffer throughout disease progression. This increase in stiffness has been shown to correlate to malignant phenotype and epithelial-to-mesenchymal transition (EMT) in vitro. Unlike current models, utilizing static increases in matrix stiffness, our group has previously created a system that allows for dynamic stiffening of an alginate–matrigel composite hydrogel to mirror the native dynamic process. Here, we utilize this system to evaluate the role of matrix stiffness on EMT and metastasis both in vitro and in vivo. Epithelial cells were seen to lose normal morphology and become protrusive and migratory after stiffening. This shift corresponded to a loss of epithelial markers and gain of mesenchymal markers in both the cell clusters and migrated cells. Furthermore, stiffening in a murine model reduced tumor burden and increased migratory behavior prior to tumor formation. Inhibition of FAK and PI3K in vitro abrogated the morphologic and migratory transformation of epithelial cell clusters. This work demonstrates the key role extracellular matrix stiffening has in tumor progression through integrin signaling and, in particular, its ability to drive EMT-related changes and metastasis.

The molecular mediators of type 2 epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology

2010 ◽  
Vol 12 ◽  
Author(s):  
Wendy C. Burns ◽  
Merlin C. Thomas
Keyword(s):  
Kidney Disease ◽  
Transcriptional Activation ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Cell Contact ◽  
Mesenchymal Transition ◽  
Tubular Cells

Common to all forms of chronic kidney disease is the progressive scarring of the tubulo-interstitial space, associated with the acquisition and accumulation of activated myofibroblasts. Many of these myofibroblasts are generated when tubular epithelial cells progressively lose their epithelial characteristics (cell–cell contact, microvilli, tight-junction proteins, apical–basal polarity) and acquire features of a mesenchymal lineage, including stress fibres, filopodia and augmented matrix synthesis. This process, known as epithelial to mesenchymal transition (EMT), plays an important role in progressive kidney disease. For EMT to occur in tubular cells, the transcriptional activation (and derepression) of genes required to sustain mesenchymal-type structures and functions (e.g. vimentin, α-smooth muscle actin) must occur alongside repression (or deactivation) of genes that act to maintain the epithelial phenotype (e.g. E-cadherin, bone morphogenic protein 7). Several factors have been suggested as potential initiators of EMT. With a few key exceptions, these triggers require the induction of transforming growth factor β (TGF-β) and downstream mediators, including SMADs, CTGF, ILK and SNAI1. Activation of TGF-β receptors is also able to stimulate a range of additional pathways (so-called non-SMAD activation), including RhoA, mitogen-activated protein kinase and phosphoinositide 3-kinase signalling cascades, that also contribute to EMT and renal fibrogenesis. This review examines in detail the molecular mediators of EMT in tubular cells and its potential role as a long-lasting mediator of metabolic stress.

scholarly journals Abstract 1087: Semaphorin 3C drives invasiveness in prostate cells through epithelial-to-mesenchymal transition and stemness

2018 ◽  
Author(s):  
Kevin J. Tam ◽  
Daniel H. Hui ◽  
Wilson C. Lee ◽  
Mingshu Dong ◽  
Tabitha Tombe ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Prostate Cells

Multi-Scale Modeling of Cancer Cell Migration and Adhesion During Epithelial-to-Mesenchymal Transition

2011 ◽  
Author(s):  
Rachel Zielinski ◽  
Cosmin Mihai ◽  
Samir Ghadiali
Keyword(s):  
Cell Migration ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Formation ◽  
Cell Stiffness ◽  
Migration And Invasion ◽  
Limited Information ◽  
Primary Tumor Site ◽  
Mesenchymal Transition ◽  
Secondary Tumor ◽  
Cell Cell

Cancer is a leading cause of death in the US, and tumor cell metastasis and secondary tumor formation are key factors in the malignancy and prognosis of the disease. The regulation of cell motility plays an important role in the migration and invasion of cancer cells into surrounding tissues. The primary modes of increased motility in cancerous tissues may include collective migration of a group of epithelial cells during tumor growth and single cell migration of mesenchymal cells after detachment from the primary tumor site [1]. In epithelial cancers, metastasizing cells lose their cell-cell adhesions, detach from the tumor mass, begin expressing mesenchymal markers, and become highly motile and invasive, a process known as epithelial-to-mesenchymal transition (EMT) (Fig. 1) [2]. Although the cellular and biochemical signaling mechanisms underlying EMT have been studied extensively, there is limited information about the biomechanical mechanisms of EMT. In particular, it is not known how changes in cell mechanics (cell stiffness, cell-cell adhesion strength, traction forces) influence the detachment, migration and invasion processes that occur during metastasis.

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