MBLab

Cell migration plays a key role in a wide variety of biological phenomena that take place during both embryogenesis and in the adult organism. Both during development and in the adulthood, cells can move individually or collectively. In addition, they can use as substrate for their movement either extracellular matrix (ECM) components or other cells. Finally, cell migration, a fascinating process in normal cells, involving numerous intricately coordinated and controlled processes, becomes destructive and damaging when acquired by cancerous cells. In our lab, we use the migration of different cell populations from the embryo and the adult for the in vivo study of the mechanisms regulating individual and collective cell migratory processes. Among the interests of the lab are:

1. To understand the role of the basement membrane (BM), a specialized extracellular matrix lining all organs and tissues, on cell migration. We have shown that the BM laid down by the embryonic hemocytes acts as a substratum to direct their individual migration and dispersion throughout the whole embryo.

The follicular epithelium of the Drosophila ovary has emerged as a genetic tractable model system to study collective cell migration. Drosophila females have two ovaries consisting of 15–20 strings of egg chambers of increasing stages of maturity. Each egg chamber is composed of a monolayer of somatic follicle cells (FCs), known as the follicular epithelium (FE), surrounding a cyst of 16 interconnected germline cells. The FE is itself surrounding by an encasing BM. During egg chamber development there are two processes of collective cell migration. During early oogenesis, the FE moves collective over the BM in a process known as global tissue rotation. Our recent results have shown that the stiffness of this BM regulates the initiation and speed of this collective example of cell migration.

Later in oogenesis, a group of 6 to 8 FCs delaminate from the FE and migrate collectively through the germline cells. In the lab, we have have recently found that the stiffness of the BM also regulate the migration of BCs by influencing the mechanical properties of the germline cells. This work reveals the remarkable and assorted ways whereby BMs can regulate cell migration during morphogenesis.

We are now investigating the molecular and cellular mechanisms underlying the different roles of BMs.

2. To isolate genes regulating invasive behaviour of cancer cells. By using the larval wing disc and gut of the Drosophila larvae as model systems, we have identified a number of candidate genes that when downregulated increase the tumurogenic capacity of oncogenic RasV12 cells. We have recently isolated mutants in these genes using the crisper-Cas9 technique. At present, we are analysing the molecular and cellular mechanisms by which alterations in these genes leads to an invasive behaviour of RasV12 cells.

Shaping tissues and organs requires forces with proper directionality, generated by the contraction of actin filament (F-actin) meshworks by the molecular motor Myosin II. The magnitude, direction and timing of contractile forces depend on the organization of the cellular actomyosin meshworks and how these networks are connected between cells and to the extracellular matrix (ECM). In the lab, we are interested in understanding the mechanisms by which interactions with the BMs contribute to the generation of cell and tissue shape, by providing a physical scaffold to oppose the contractile forces generated by epithelial cell shape changes.
To address these issues, we use a multidisciplinar approach combining genetics with cell and molecular biology, biophysical measurements, in vivo imaging and mathematical modelling. At present, we concentrate on the following aspects of tissue morphogenesis:

1. Role of cell-BM interactions mediated by integrins on the morphogenesis and homeostasis of mono-layered epithelium. Our results have identified a key role for integrins on the maintenance of the FE. Using live imaging and newly developed fluorescent markers, we are following in vivo cell division and, in particular, positioning of the mitotic spindle, in wild type and integrin mutant FCs. Our recent results suggest that tissue tension might play a role in this context. At present, we are testing this hypothesis applying live microscopy, imaging analysis and mathematical and in silico modeling, to both wild type and conditions in which tension is affected in specific areas of the FE.

2. Role of integrins as regulators of acto-myosin activity in epithelia morphogenesis and homeostasis. Morphogenesis, function and maintenance of epithelia require a fine balance between acto-myosin contraction forces and opposing integrin adhesion forces. In fact, we have found that elimination of integrin function in the wing imaginal disc epithelium leads to cell death. However, we have also discovered that downregulation of integrins caused changes in acto-myosin activity and cell shape that leads to basal folding. We propose that normal morphogenesis require a tightly regulated removal from the restrain of ECM contacts. We are currently testing this hypothesis.