University of Dundee

The importance of separation: implications for colon cancer

15 Nov 2017

Maintenance of tissues requires a delicate balance between a number of processes such as the increase in the number of cells (proliferation) and the type of cells they become (differentiation).  Changes in this balance can lead to tumour formation.  Work from Professor Inke Näthke and her colleagues in the Division of Cell and Developmental Biology focussing on the intestinal tract and on colon cancer has shed further light on this area. 

The work, published today in Journal of Cell Science, provides evidence for the importance of a new mechanism that controls the position of intestinal cells in the lining of the gut (called epithelium).  The group; in collaboration with Dr James Osborne, Melbourne Australia who performed the modelling work; studied the positioning of daughter cells after they are born, i.e. after cell division.  When epithelial cells start to divide, their nuclei migrate upwards away from their normal position near the bottom of the epithelial layer, towards the surface of the epithelial layer that faces the gut lumen.  That cell then divides into two newly formed cells that either remain next to each other or separate during their movement towards the bottom of the epithelial layer.  This separation occurs in about 30% of cases in a “normal” situation.  Experimental observation and computational modelling showed that this separation leads to more diverse cell pairs than the adjacent placement. 

When mutant epithelial cells were examined, different outcomes were observed.  Specifically, cells were studied that contained a mutated version of a protein called adenomatous polyposis coli (Apc), which has many diverse functions including a role in differentiation.  These mutations occur at extremely early stage of inherited as well as most sporadic colon cancers.  The study found that in Apc mutant epithelia, cells no longer separate.  Together with the decreased migration of these mutant cells this explains why daughters of Apc mutant cells are retained where they are born.  That means they colonise proliferative niches more effectively than non-mutant cells and this allows them to ‘take over’ such niches and initiate polyps, the earliest stage of transformation. 

Professor Näthke said, “This paper resulted from Thomas Carroll’s first rotation in my lab on his MRC PhD program.  During his subsequent PhD work, for which he was jointly supervised by Julian Blow and myself, he extended ideas that emerged from the rotation to make the discovery related to the post-mitotic placement of daughter cells.  This work laid the foundation (technically and scientifically) for his major PhD project that produced another major publication that we hope we can share with the school soon.”
 
High-resolution fluorescence microscopy was an important technique used in the study.  It produced an image that was selected for the issue cover (pictured).  In addition, the paper was highlighted in the ‘In This Issue’ section of the journal.

Journal of Cell Science :”Interkinetic nuclear migration and basal tethering facilitates post-mitotic daughter separation in Intestinal Organoids”
Thomas D Carroll, Alistair J Langlands, James M Osborne, Ian P Newton, Paul L Appleton, and Inke Näthke.

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