Research

How do collectives maintain their shape and ability to move within confined tissues?

control egg chamberDIC2Y

Collectives need to stay together and keep their shape, all while moving through confined environments. Border cells (light yellow, picture at right) are 6-10 cells that move as a group between large “nurse cells” to navigate towards the oocyte (large cell to upper right of picture). We recently discovered a role for dynamic myosin at the outer edges of the border cell collective to resist the compression provided by the surrounding nurse cells. We want to understand what triggers transient myosin enrichment specifically at the outside of the collective. In addition, are there other cytoskeletal regulatory proteins that influence the shape of the collective? How do individual border cells maintain shape during this process? And how does mechanical feedback between border cells and nurse cells influence border cell migration?

Reading:

Dynamic myosin activation promotes collective morphology and migration by locally balancing oppositional forces from surrounding tissue.  Aranjuez G, Burtscher A, Sawant K, Majumder P, McDonald JA. Mol. Biol. Cell 2016 27(12): 1898-1910. doi: 10.1091/mbc.E15-10-0744.


How do cells break away from epithelia to become migratory?

An unresolved but critical question is how groups of cell break away from epithelia to begin their migratory journey. This occurs in tumor invasion and metastasis as well as certain aspects of development.

Stills from movie of live border cell migration

Border cells represent an ideal system to image this process in real-time and to manipulate the cells in their native environment. We recently discovered that the polarity protein and serine-threonine kinase Par-1 regulates two aspects of detachment: cell polarity-dependent remodeling of adhesion and myosin-dependent contraction. Currently we are investigating the opposing roles of two small GTPases in this process.

Reading:

PAR-1 kinase regulates epithelial detachment and directional protrusion of migrating border cells. McDonald JA, Khodyakova A, Aranjuez G, Dudley C, Montell DJ. Curr Biol. 2008 Nov 11;18(21):1659-67. doi: 10.1016/j.cub.2008.09.041.

Par-1 controls myosin-II activity through myosin phosphatase to regulate border cell migration. Majumder P, Aranjuez G, Amick J, McDonald JA. Curr Biol. 2012 Mar 6;22(5):363-72. doi: 10.1016/j.cub.2012.01.037.


How do single cells come together and communicate to produce group movement?

HoImaris Snapshotw do normal and cancerous cells stay together to move as a group rather than as single cells? Our lab recently discovered a mutant in which, when the gene is knocked down, the border cells round up, separate from each other and begin to function as individual cells. We are currently investigating the mechanisms for how this genetic pathway controls adhesion between cells, maintains individual cell shapes, and keeps the border cell group moving.


Interplay of polarity and cytoskeletal regulatory proteins

How do proteins that control cell polarity interface with the cytoskeleton during cell migration? Do these proteins function differently in collective cell migration? To address these questions, we recently undertook an RNAi screen for G3 Cover November 2012 (Aranjuez et al.)genes required for collective border cell migration. We particularly targeted genes that encode PDZ- (PSD95/DLG/ZO-1) domain containing proteins, because these proteins serve as large protein scaffolds that modulate cell polarity, cell junctions and the cytoskeleton. We identified 14 genes whose knockdown by RNAi impaired border cell migration. These included known regulators of border cell collective migration such as Par-3 (Baz) and Par-6. Current projects in the lab focus on characterizing novel genes from this screen with roles in cell adhesion, signaling and cytoskeletal regulation.

Reading:

On the role of PDZ domain-encoding genes in Drosophila border cell migration. Aranjuez G, Kudlaty E, Longworth MS, McDonald JA. G3 (Bethesda). 2012 Nov;2(11):1379-91. doi: 10.1534/g3.112.004093.

M.T. Veeman and J.A. McDonald: Dynamics of cell polarity in tissue morphogenesis: a comparative view from Drosophila and Ciona. F1000Research. 2016 Jun 2; 5. pii: F1000 Faculty Rev-1084. doi: 10.12688/f1000research.8011.1. eCollection 2016.


Application of Drosophila border cell model to tumor invasion

Using genes we have already discovered, along with new RNAi screens, we are applying our discoveries in border cell collective migration to human tumor invasion. This is a collaborative project with several basic and translational cancer researchers at the Cleveland Clinic Lerner Cancer cell invasionResearch Institute. We have found that some patient-derived tumor cell lines invade as single cells (left panel) in culture, whereas others invade in finger-like ‘collective’ strands (right panel). We are using genes found in border cells to identify those upregulated in human glioma patients. We hope to discover genes that control the transition between collective and single cell invasion and understand the impact these genes have on disease progression.