Basal extrusion drives cell invasion and mechanical stripping of E-cadherin

John Fadul, Gloria M Slattum, Nadja M Redd, Teresa F Zulueta-Coarasa, Michael Redd, Stephan Daetwyler, Danielle Hedeen, Jan Huisken, Jody Rosenblatt

Preprint posted on 6 November 2018

Kicking out oncogenic cells may promote the spread of tumours

Selected by William Hill


Oncogenesis can start with a mutation to a single cell, resulting in a transformed malignant cell, within a healthy epithelial sheet. It is increasingly apparent that single transformed cells can be detected and squeezed out of the tissue by the surrounding normal neighbours. This process has been observed in flies, cell lines, organoids, zebrafish and in vivo using mouse models (Bielmier et al., 2016; Hogan et al., 2009; Kon et al., 2017; Anton et al., 2018).

Single, oncogenic cells can be extruded either apically or basally.


However, what is less clear is the fate of extruded cells. It is currently thought that the direction of extrusion can impact an extruded cells’ fate; if a cell is pushed out apically then it dies or is cleared through the lumen. However, it is unclear what happens to cells that extrude basally.

In this preprint, the authors investigate the fate of KRas-transformed cells surrounded by normal neighbours in zebrafish. Expression of different oncogenes was combined with fluorescent markers to track mutant cells in real-time. Oncogenes which promote extrusion are associated with metastatic cancers so the authors hypothesise that basal extrusion could be a novel mechanism of metastasis.

Key findings of the preprint

KRas-transformed cells can be extruded basally and apically and initiate tumourigenesis.

Firstly, the authors injected EGFP-KRasV12 plasmids driven by the krt4 promoter into one-cell embryos to generate mosaic expression of KRas in epidermal cells. They found that this was sufficient to form cell masses in 58% of zebrafish embryos compared to 1% of EGFP-CAAX controls. Time-lapse imaging of labelled cells over time revealed that KRasV12 cells can extrude both apically and basally, although significantly more basal extrusions were observed. They saw that basal extrusion can lead to invasion and internalisation of mutant cells into different parts of the zebrafish. Although KRas-transformed cells could form cell masses, a large number of mutant cells were lost over time, which could be a result of extrusion observed in time-lapse imaging.

Loss of p53 promotes the survival extruded cells.

During the evolution of cancer, transformed cells accumulate additional mutations which drive tumourigenesis. To model this the authors combined expression of KRasV12 with depletion of p53 via a translation-blocking morpholino. This led to a reduction in basal extrusion of aberrant cells. However, loss of p53 increased the survival of basally invading cells and their ability to survive as internalised masses at later time points.

Extruded cells can spread through the bloodstream and may initiate EMT

After establishing the system, the authors began characterising cells that invade basally. They found that all internalised cells lose the epithelial marker E-cadherin and a small subset expressed the mesenchymal marker N-cadherin. Intriguingly, time lapse imaging in combination with a vasculature reporter was used to identify GFP-KRasV12 cells in the bloodstream with 65% of 42 zebrafish having circulating cells. Finally, using different fluorescent markers for the apical and cytoplasm it was observed that the apical membrane is ripped off during extrusion and the remainder of the cell migrates away. The authors suggest that basal extrusion drives invasion of KRasV12 cells and strips off the apical surfaces and associated E-cadherin.

What I like about this preprint

This preprint demonstrates that extrusion can lead to mutant cells in the circulation of zebrafish, which is a possible new way for oncogenic cells to spread around the body. Although lots of work on the mechanism of extrusion has been carried out, this paper begins to characterise the fate of extruded cells.

The authors looked at how the mechanical force of KrasV12 cells being squeezed out constricts the nucleus and can scrape off the E-cadherin apical membrane proteins. This sudden loss of the apical membrane could have important implications for metastasis and EMT.

I also liked the great videos of cells extruding from zebrafish!

Questions to the authors

What do you think could be regulating whether mutant cells either accumulate into masses or extrude in the different parts of the zebrafish?

In the movies do you ever see KRasV12 cells extravasate from the circulation?

Mechanical stretch can promote YAP translocation into the nucleus, have you looked for YAP nuclear localisation in extruding cells?


Anton, K. A., Kajita, M., Narumi, R., Fujita, Y., & Tada, M. (2018). Src-transformed cells hijack mitosis to extrude from the epithelium. Nature communications, 9(1), 4695.

Bielmeier, C., Alt, S., Weichselberger, V., La Fortezza, M., Harz, H., Jülicher, F., … & Classen, A. K. (2016). Interface contractility between differently fated cells drives cell elimination and cyst formation. Current Biology, 26(5), 563-574.

Hogan, C., Dupré-Crochet, S., Norman, M., Kajita, M., Zimmermann, C., Pelling, A. E., … & Hosoya, H. (2009). Characterization of the interface between normal and transformed epithelial cells. Nature cell biology, 11(4), 460.

Kon, S., Ishibashi, K., Katoh, H., Kitamoto, S., Shirai, T., Tanaka, S., … & Kamasaki, T. (2017). Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. Nature cell biology, 19(5), 530.

Tags: cell competition, extrusion, zebrafish

Posted on: 2 January 2019


Read preprint (No Ratings Yet)

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the cancer biology category:

Also in the cell biology category:

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.


List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.


List by Nadja Hümpfer et al.


The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!


List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.


List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020


List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.


List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria


List by Dey Lab, Samantha Seah


Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.


List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20


List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.


List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome


List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)


List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019


List by Dey Lab


Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.


List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.


List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.


List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019


List by Dey Lab


This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.


List by Sandra Franco Iborra

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.


List by Dey Lab, Amanda Haage