Snail induces epithelial cell extrusion through transcriptional control of RhoA contractile signaling and cell matrix adhesion

Background:

Cell extrusion is one of the key processes that maintain epithelial homeostasis, but on the other hand is also responsible for inducing tumor metastasis. It is becoming clear that cell-extrusion is a phenomenon that is regulated by acto-myosin contractility. Cells can extrude apically or basally from the epithelium. Apical extrusion versus basal delamination is dependent on the number of cell intrinsic factors including contractility, cell polarity but also on cell-cell adhesion and cell-matrix interactions (Gudipaty and Rosenblatt 2017). Transcription factors like Snail are known to regulate these cell intrinsic parameters. However, role of transcriptional regulation in cell extrusion is not very well understood.

Major findings:

Authors report that when MCF-7 epithelial cells are induced with stable Snail expression, uniform expression in many cells lead to basal delamination whereas expression in few cells cause apical extrusion. Interestingly the extruded cells maintain the epithelial integrity and no changes in the E-Cadherin levels were observed. Extruded cells show an increase in the RhoA contractile pathway and thus an increase in the levels of actin and phosphorylated non muscle MyoII. They also show that Snail expression causes RhoA activation in cell-autonomous manner that leads to increase in contractility in the cells. Concomitant with that phospho-dead expression of MyoII decreases extrusion and shows decrease in the adhesion proteins like Paxillin. The study shows role of increased contractility with de-adhesion regulated by Snail is responsible for cell extrusion.

What I liked about the preprint

This pre-print elucidates the role of transcriptional regulation in cell extrusion. It is interesting that while that happens, cells maintain the epithelial integrity and do not undergo epithelial to mesenchymal transition. Proper directional and balanced cell extrusion is important for fate determination and cancer outcomes and this study provides an interesting view on how directional cell extrusion can be regulated by the number of cells expressing transcription factors and thus Rho signaling, contractility and adhesion.

What’s next and my questions to the author:

It is interesting that the number of Snail expressing cells decide the direction of extrusion. From the literature it suggests that, this could happen because of the disruption of polarity in the extruding cells. For example, disruption of microtubules can also reverse the direction of extrusion, because of the improper GEF localization (Marshall et al. 2011).

• I was curious what happens to the polarity of the cells expressing Snail in mosaic, that ultimately extrude apically. Is it different from the polarity of the cells expressing Snail uniformly in the monolayer which ultimately leads to basal extrusion/delamination?
• According to the experiments performed by the authors, cells expressing Snail cell-autonomously regulate contractility, so how do cells make a decision of whether to extrude apically or delaminate?
• Interestingly, cells expressing phosphor-dead mutant of MyoII decrease extrusion apically (when expressed in mosaic) but when phosphomimetic MyoII was expressed in the monolayer cells, there is no increase in the delamination. What about if these mutants (MRLC^DD) were expressed in mosaic?
• Since there are no changes in the expression levels of E-cadherin in the cells undergoing extrusion, I was wondering if delamination occurs because of the mis-localization of E-cadherin in the extruding/delaminating cells since E-cadherin mediated mechanical signals instruct junctional actomyosin for extrusion/delamination (Lubkov and Bar-Sagi 2014).

Gudipaty, Swapna Aravind, and Jody Rosenblatt. 2017. “Epithelial Cell Extrusion: Pathways and Pathologies.” Seminars in Cell & Developmental Biology 67 (July): 132–40.

Lubkov, Veronica, and Dafna Bar-Sagi. 2014. “E-Cadherin-Mediated Cell Coupling Is Required for Apoptotic Cell Extrusion.” Current Biology: CB 24 (8): 868–74.

Marshall, Thomas W., Isaac E. Lloyd, Jean Marie Delalande, Inke Näthke, and Jody Rosenblatt. 2011. “The Tumor Suppressor Adenomatous Polyposis Coli Controls the Direction in Which a Cell Extrudes from an Epithelium.” Molecular Biology of the Cell 22 (21): 3962–70.

Tags: cell extrusion, contractility, delamination, transcription factors

Posted on: 6th May 2019

Read preprint (No Ratings Yet)