Thompson lab image.

Barry Thompson : When epithelial cells become invasive

Introduction

We sought to understand how invasive migration occurs in border cells. We focused on the actin cytoskeleton, which is crucial for cell migration and is highly polarised along the apical-basal axis of each border cell.

In particular, the actin cytoskeleton is most prominent and dynamically active at the basal surface of each border cell, forming a rim around the entire cluster.

Most human cancers arise in epithelial tissues, which progress to metastasis when epithelial cells manage to invade their surroundings and become migratory. The fruit fly, Drosophila, offers an excellent model system for epithelial invasion: the migration of a cluster of 'border cells'.

Border cells are a group of 6-8 epithelial cells that are specified in the follicular epithelium that surrounds each egg chamber of the Drosophila ovary. The border cells subsequently become invasive and migrate from their initial location at the anterior pole of the egg chamber towards the posterior pole, where the oocyte is located. During migration of the border cell cluster, the epithelial cells retain their apical-basal polarity - similar to migrating clusters of human cancer cells.

Invasive migration of Drosophila border cells.

Figure 1: Invasive migration of Drosophila border cells. A. Border cells (green) migrate across the egg chamber during stage 9 of oogenesis. F-actin is labelled in red, nuclei in blue. B. Apical-basal polarity in border cell clusters. F-actin (red) is polarised around the outer rim of the cluster. Hippo pathway components (green) are localised to inner membranes, where they act to restrict F-actin polymerisation.

We sought to understand how invasive migration occurs in border cells. We focused on the actin cytoskeleton, which is crucial for cell migration and is highly polarised along the apical-basal axis of each border cell. In particular, the actin cytoskeleton is most prominent and dynamically active at the basal surface of each border cell, forming a rim around the entire cluster.

It was clear that this apical-basal polarisation of the actin cytoskeleton relies on the fundamental molecular determinants of apical-basal polarity, such as the apical Cdc42-aPKC-Par6 complex. Yet, how these molecules control the actin cytoskeleton was not known.

We have now identified a key role for the Hippo signalling pathway in linking determinants of apical-basal polarity with polarisation of the actin cytoskeleton. We find the upstream components of the Hippo pathway co-localise with apical polarity determinants and mediate a signalling cascade involving the Ena/VASP family of proteins that restricts activation of actin polymerisation to the basal side of the cell.

When Hippo signalling is disrupted, the F-actin cytoskeleton is no longer correctly polarised and accumulates abnormally around the entire plasma membrane to disrupt the collective migration of the border cell cluster.

Intriguingly, there is also a role for the nuclear Hippo pathway effector, Yorkie (Yki)/YAP, in sensing events at the plasma membrane and providing feedback to regulate migration. Consequently, over-expressing Yorkie/YAP causes border cells to accelerate their invasive migration.

These findings identify a novel role for the Hippo pathway in cell polarity and collective cell migration in vivo. These findings have relevance for human cancer, where the Hippo pathway has already been implicated in controlling stem cell proliferation and tissue growth. Further examination of this pathway in cancer should now also consider its potential role in promoting invasive migration of cancer cells.