Epithelial Cell Polarity & Tissue Maintenance

Lead Research Organisation: University College London

Abstract

Most of our organs consist of epithelial cells, which are able to adhere to one another to form tissues. Because these cells are so common, it is not surprizing that most cancers come from epithelial tissues, including the intestine, kidney, breast pancreas, lung and skin to name a few. In order to form tissues and stay in place, epithelial cells need to form adhesion domains on their sides so that they can stick to their neighbours. Having formed adhesion domains, these cells can now make their top surface different from their bottom surface. Together with adhesion, the polarization of the epithelial cells is needed for them to work properly. Loss of polarity and adhesion is a hallmark of cancer and pathologists have long relied on assessing epithelial cell shape to diagnose of this disease. Work in our research group focuses on uncovering the mechanisms that regulate polarity and adhesion in epithelial cells. By understanding these mechanisms we will be able to figure out what goes wrong with these cells when cancer arises, and we will be better equipped to prevent or fix the problem.

Technical Summary

Apical-basal polarity is essential for epithelial cell function, and in epithelial tissues its loss is a hallmark of cancer. The overall aim of our research group is to elucidate how polarity arises in epithelial cells and how it is maintained in mature tissues. To this end we combine work in Drosophila tissues and human cell lines, using optogenetic, biophysical methods and super resolution imaging approaches. With this three-year funding support, our goal is to address the following specific aims: (1) Explore the extent to which regulated nuclear export of polarity factors acts as a main mechanism of cell polarity in animal cells. We have obtained evidence that regulated RanGTP-dependent nucleocytoplasmic transport and in particular release of the polarity protein PAR4/LKB1 from the nuclear export machinery regulates epithelial polarity. We will determined how exactly this new polarity mechanism operates and how widespread it’s function is during polarized cell morphogenesis (2) Test whether the PAR complex acts as a receptor for the exocyst to translate polarity at the cell cortex into plasma membrane morphogenesis, including cell-cell contact maturation. We have recently discovered that in components of the conserved PAR complex binds to subunit of the exocyst. The exocyst is an octameric complex that is conserved across phyla and promotes membrane delivery, raising the possibility that the PAR complex regulates cargo delivery during polarized morphogenesis. Altogether, our two research aims to elucidate the mechanisms that generate epithelial polarity and maintain epithelial tissue integrity, a prerequisite for understanding epithelial cells function and how defects in polarity and tissue integrity impact on human diseases such as cancer.
 
Description Benchtop, turnkey super-resolution microscopy for biology, biophysics and biotechnology
Amount £203,370 (GBP)
Funding ID BB/T01749X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2020 
End 06/2021
 
Description Enabling imaging of cells and tissues across scales
Amount £333,750 (GBP)
Funding ID 218278/Z/19/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 08/2024
 
Title Tension- elastic model of lens morphogenesis during eye development. 
Description Tension-elastic Molde of lens development. 
Type Of Material Computer model/algorithm 
Year Produced 2019 
Provided To Others? Yes  
Impact Will allow us to simulate the mechanical properties of retinal cells during lens development. 
 
Title Vertex model lens morphogenesis during eye development 
Description Vertex Model of lens morphogenesis. 
Type Of Material Computer model/algorithm 
Year Produced 2019 
Provided To Others? Yes  
Impact Will allow us to simulate cell shape changes and mechanics of retinal cells as they work together to generate the lens. 
 
Description AFM to study force regulation during photoreceptor morphogenesis. 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are collaborating with the lab of Guillaume Charras to explore how mechanical constraints help shaping neurons (Photoreceptors), during development.
Collaborator Contribution Prof Charras is helping us maing use of Atomic Force Microscopy to apply forces onto retina cells. This is to test our model that mechanical forces hel shaping photoreceptors during retinal development.
Impact AFM prove to be suboptimal to address our research question.
Start Year 2018
 
Description Mathematical model of eye development 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with the lab of Dr Yanlan Mao to generate a new mathematical Molde of Drosophila eye development. Our web contributed all the work that was required for setting up the model: measures of cortical tension and adhesion between retinal cells.
Collaborator Contribution Dr Mao's lab generated the mathematical model (Vertex model) to simulate lens morphogenesis during eye development.
Impact This collaboration translated into a research paper that is now in revision with the journal 'Development'.
Start Year 2017
 
Description Mathematical model of retinal cell shape and mechanics 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We generated all the measurements (tension, cell shape) that were required to set up a new computational model of retinal cell shape and morphogenesis.
Collaborator Contribution Dr Shiladitya Banerjee generated a new tension-elastic model of retinal cell shape change during development.
Impact This work has now been published.
Start Year 2018
 
Description Mechanisms of neuronal polarity 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We discovered that nuclear export of polarity factors direct cortical neuron polarity
Collaborator Contribution The Riccio lab helped us with in vivo work on the nuclear export pathway during neuronal polarity.
Impact We have now published our work showing that cortical neuron polarity is initiated by the nuclear export of the polarity protein LKB1 (Mencarelli et al., 2016- Cell repports). We are now preparating a follow up manuscript that report that nuclear export of LKB1 is also a key step during directed migration of neural crest cells during development.
Start Year 2017
 
Description Neural Crest cell migration 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are collaborating with the lab of Roberto Mayor at UCL (CDB) to characterize the role of the nuclear export machinery during polarized cell migration in vivo.
Collaborator Contribution The lab of R. Mayor has helped us making use of Zebrafish and Xenopus to study the mechanisms of neural crest cell migration in vivo during development.
Impact We have prepared a manuscript that reports that nuclear export of LKB1 is a key step during directed migration of neural crest cells during development. We will submit this paper in 2021.
Start Year 2018
 
Description Super Resolution Lattice sheet microscopy 
Organisation Medical Research Council (MRC)
Department MRC Cell Biology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We are contributing biological samples and expertise relevant to the development of this new super resolution live imaging system. Our latest new development has been to image leaving developing Drosophila (retina) using the lattice light sheet.
Collaborator Contribution Our collaborator is developing new algorithms to enable live super resolution imaging of cells through lattice sheet microscopy.
Impact Through our collaborator who operate this micorscope, we have now generated 6 research publications. We are working toward imaging exocystosis in live epithelial cell cysts.
Start Year 2018
 
Description MRC blog featuring research in my lab 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact wrote a blog in collaboration with the MRC.
Year(s) Of Engagement Activity 2018
URL https://www.insight.mrc.ac.uk/
 
Description Meet and Greet - Princesse Royal Anne. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Meet and greet Princess Royal - opening of a new imaging centre at UCL, for which I am the academic lead.
Year(s) Of Engagement Activity 2020
 
Description Sir Keir Starmer 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact Meet and greet with Sir Keir Starmer- Shadow Secretary of State for Exiting the European Union.
Discussion focussed on the use of Molde organisms (Drosophila, fish, mouse) in biomedical research, on university campuses.
Year(s) Of Engagement Activity 2019