scholarly journals Ectoderm to mesoderm transition by down-regulation of actomyosin contractility

PLoS Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. e3001060
Author(s):  
Leily Kashkooli ◽  
David Rozema ◽  
Lina Espejo-Ramirez ◽  
Paul Lasko ◽  
François Fagotto
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Specific Property ◽  
Tissue Level ◽  
Small Gtpase ◽  
Collective Migration ◽  
Down Regulation ◽  
Mesenchymal Transition ◽  
Cortical Tension ◽  
Actomyosin Contractility ◽  
Rock Inhibition

Collective migration of cohesive tissues is a fundamental process in morphogenesis and is particularly well illustrated during gastrulation by the rapid and massive internalization of the mesoderm, which contrasts with the much more modest movements of the ectoderm. In the Xenopus embryo, the differences in morphogenetic capabilities of ectoderm and mesoderm can be connected to the intrinsic motility of individual cells, very low for ectoderm, highly for mesoderm. Surprisingly, we find that these seemingly deep differences can be accounted for simply by differences in Rho-kinases (Rock)-dependent actomyosin contractility. We show that Rock inhibition is sufficient to rapidly unleash motility in the ectoderm and confer it with mesoderm-like properties. In the mesoderm, this motility is dependent on 2 negative regulators of RhoA, the small GTPase Rnd1 and the RhoGAP Shirin/Dlc2/ArhGAP37. Both are absolutely essential for gastrulation. At the cellular and tissue level, the 2 regulators show overlapping yet distinct functions. They both contribute to decrease cortical tension and confer motility, but Shirin tends to increase tissue fluidity and stimulate dispersion, while Rnd1 tends to favor more compact collective migration. Thus, each is able to contribute to a specific property of the migratory behavior of the mesoderm. We propose that the “ectoderm to mesoderm transition” is a prototypic case of collective migration driven by a down-regulation of cellular tension, without the need for the complex changes traditionally associated with the epithelial-to-mesenchymal transition.

scholarly journals Ectoderm to mesoderm transition by downregulation of actomyosin contractility

2019 ◽  
Author(s):  
Leily Kashkooli ◽  
David Rozema ◽  
Lina Espejo-Ramirez ◽  
Paul Lasko ◽  
François Fagotto
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Specific Property ◽  
Tissue Level ◽  
Small Gtpase ◽  
Collective Migration ◽  
Mesenchymal Transition ◽  
Cortical Tension ◽  
Actomyosin Contractility ◽  
Fundamental Process ◽  
Rock Inhibition

SummaryCollective migration of cohesive tissues is a fundamental process in morphogenesis, and is particularly well illustrated during gastrulation by the rapid and massive internalization of the mesoderm, which contrasts with the much more modest movements of the ectoderm. In the Xenopus embryo, the differences in morphogenetic capabilities of ectoderm and mesoderm can be connected to the intrinsic motility of individual cells, very low for ectoderm, highly for mesoderm. Surprisingly, we find these seemingly deep differences can be accounted for simply by differences in Rock-dependent actomyosin contractility. We show that Rock inhibition is sufficient to rapidly unleash motility in the ectoderm and confer it with mesoderm-like properties. In the mesoderm, this motility is dependent on two negative regulators of RhoA, the small GTPase Rnd1 and the RhoGAP Shirin/Dlc2/ArhGAP37. Both are absolutely essential for gastrulation. At the cellular and tissue level, the two regulators show overlapping yet distinct functions. They both contribute to decrease cortical tension and confer motility, but Shirin tends to increase tissue fluidity and stimulate dispersion, while Rnd1 tends to favour more compact collective migration. Thus, each is able to contribute to a specific property of the migratory behaviour of the mesoderm. We propose that the “ectoderm to mesoderm transition” is a prototypic case of collective migration driven by a downregulation of cellular tension, without the need for the complex changes traditionally associated with the epithelial to mesenchymal transition.

scholarly journals Neuralized regulates a travelling wave of Epithelium-to-Neural Stem Cell morphogenesis in Drosophila

2020 ◽  
Author(s):  
Chloé Shard ◽  
Juan Luna-Escalante ◽  
François Schweisguth
Keyword(s):  
Stem Cells ◽  
Ubiquitin Ligase ◽  
Epithelial To Mesenchymal Transition ◽  
Optic Lobe ◽  
E3 Ubiquitin Ligase ◽  
Tissue Level ◽  
Travelling Wave ◽  
Cell Morphogenesis ◽  
Apical Constriction ◽  
Mesenchymal Transition

AbstractMany tissues are produced during development by specialized progenitor cells emanating from epithelia via an Epithelial-to-Mesenchymal Transition (EMT). Most studies have so far focused on cases involving single or isolated groups of cells. Here we describe an EMT-like process that requires tissue level coordination. This EMT-like process occurs along a continuous front in the Drosophila optic lobe neuroepithelium to produce neural stem cells (NSCs). We find that emerging NSCs remain epithelial and apically constrict before dividing asymmetrically to produce neurons. Apical constriction is associated with contractile myosin pulses and requires the E3 ubiquitin ligase Neuralized and RhoGEF3. Neuralized down-regulates the apical protein Crumbs via its interaction with Stardust. Disrupting the regulation of Crumbs by Neuralized led to defects in apical constriction and junctional myosin accumulation, and to imprecision in the integration of emerging NSCs into the transition front. Neuralized therefore appears to mechanically couple NSC fate acquisition with cell-cell rearrangement to promote smooth progression of the differentiation front.

scholarly journals Rab31-dependent regulation of transforming growth factor ß expression in breast cancer cells

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Susanne Soelch ◽  
Nathalie Beaufort ◽  
Daniela Loessner ◽  
Matthias Kotzsch ◽  
Ute Reuning ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Cancer Cell Line ◽  
Underlying Mechanism ◽  
Mrna Levels ◽  
Down Regulation ◽  
Mesenchymal Transition

Abstract Background The small GTP-binding protein Rab31 plays an important role in the modulation of tumor biological-relevant processes, including cell proliferation, adhesion, and invasion. As an underlying mechanism, Rab31 is presumed to act as a molecular switch between a more proliferative and an invasive phenotype. This prompted us to analyze whether Rab31 overexpression in breast cancer cells affects expression of genes involved in epithelial-to-mesenchymal transition (EMT)-like processes when compared to Rab31 low-expressing cells. Methods Commercially available profiler PCR arrays were applied to search for differentially expressed genes in Rab31 high- and low-expressing CAMA-1 breast cancer cells. Differential expression of selected candidate genes in response to Rab31 overexpression in CAMA-1 cells was validated by independent qPCR and protein assays. Results Gene expression profiling of key genes involved in EMT, or its reciprocal process MET, identified 9 genes being significantly up- or down-regulated in Rab31 overexpressing CAMA-1 cells, with the strongest effects seen for TGFB1, encoding TGF-ß1 (> 25-fold down-regulation in Rab31 overexpressing cells). Subsequent validation analyses by qPCR revealed a strong down-regulation of TGFB1 mRNA levels in response to increased Rab31 expression not only in CAMA-1 cells, but also in another breast cancer cell line, MDA-MB-231. Using ELISA and Western blot analysis, a considerable reduction of both intracellular and secreted TGF-ß1 antigen levels was determined in Rab31 overexpressing cells compared to vector control cells. Furthermore, reduced TGF-ß activity was observed upon Rab31 overexpression in CAMA-1 cells using a sensitive TGF-ß bioassay. Finally, the relationship between Rab31 expression and the TGF-ß axis was analyzed by another profiler PCR array focusing on genes involved in TGF-ß signaling. We found 12 out of 84 mRNAs significantly reduced and 7 mRNAs significantly increased upon Rab31 overexpression. Conclusions Our results demonstrate that Rab31 is a potent modulator of the expression of TGF-ß and other components of the TGF-ß signaling pathway in breast cancer cells.

scholarly journals Rac Inhibition As A Novel Therapeutic Strategy for EGFR/HER2 Targeted Therapy Resistant Breast Cancer

2020 ◽  
Author(s):  
Luis D Borrero-Garcia ◽  
Maria del Mar Maldonado ◽  
Julia I Medina-Velázquez ◽  
Angel Troche-Torres ◽  
Luis Velazquez-Vega ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Epithelial To Mesenchymal Transition ◽  
Point Mutations ◽  
Therapy Resistance ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Intrinsic Resistance ◽  
Mesenchymal Transition ◽  
Resistant Cells

Abstract Background Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. Methods To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. Results Gefitinib and lapatinib treatments reduced mammosphere formation in the parental cells, but not in the therapy resistant variants, indicating enhanced cancer stem cell-like and epithelial to mesenchymal transition (EMT) characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in established therapy resistant pathways of Akt and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested and found to inhibit viability and induce apoptosis of therapy resistant cells. Conclusions Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.

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