Cell adhesion, migration and extracellular matrix remodeling

What mechanisms are responsible for the formation of metastasis? How is cell migration through a complex 3D environment controlled? What are the signals and how are they presented in the tissue to influence cell adhesion and migration? What are the mechanisms that control the reversible anchorage to the extracellular matrix in migrating cells? How are receptors for the extracellular matrix anchored in the cell surface and how are they used to remodel and to deposit extracellular matrix under normal and pathological conditions such as fibrosis? How is the architecture and mechanical properties of such an extracellular matrix transformed into biochemical information controlling cell adhesion, migration and survival?

To answer these and similar questions is the goal of our research group here in the Centre Médical Universitaire. Since several years, we have been using cell biological and life-cell imaging techniques to understand how growth factors, such as Kit-ligand and extracellular matrix proteins such as fibronectin, laminin and vitronectin are presented to and recognized by receptors of the receptor tyrosine kinase or integrin families (e.g. c-kit and avb3-integrin). Both receptor systems are involved in cell adhesion, migration and survival of many cell populations in our body. Unfortunately, mutations in, or deregulation of these receptor systems can cause cancer, lead to the formation of metastasis, but are also involved in pathologies such as tissue fibrosis.

Although different in their molecular structure and regulation, both of these receptor systems can anchor cells to their environmental niches, but induce also intracellular signaling that reflects changes in composition and mechanical properties. Specifically, by binding to immobilized growth factors or extracellular matrix proteins, these receptor systems transmit information of the mechanical properties of their environment, also known as mechanosensing, which in turn creates intracellular signaling that is key to maintaining the healthy state of a tissue. However, when the composition or rigidity of the microenvironment is changing, these receptors can provide signaling that allows cancer cells to survive, even when challenged with very specific therapeutic drugs, or will perturb the normal regeneration of tissues leading to tissue fibrosis.

In order to understand how cellular microenvironments are physically altered by tumor-associated stromal cells, or by (myo)fibroblasts in chronically inflamed tissues, we have recently started to explore the cellular mechanisms that are responsible for the synthesis and deposition of extracellular matrix proteins. Interestingly, integrin receptors, which anchor cells and perceive adhesive information are also required for the normal and pathological remodeling of the extracellular matrix. However, for this task, integrins require a different set of intracellular adapter proteins that can switch their activity of mechanosensing, to reshaping of the extracellular matrix.

Our goal is to identify the critical signaling steps that control cell adhesion and migration, but also to understand how the rewiring of the intracellular integrin adapter complexes is enabling the formation of fibrotic deposition of extracellular matrix. By studying the fundamental components and their protein-protein and protein-plasma-membrane interactions, we hope to identify new therapeutic targets, which will eventually allow reverting or preventing pathological conditions, such as tissue fibrosis or the growth and invasion of tumor cells.