Understanding the role of lipids in disease to target them with drugs

Many cells in our body are subject to frequent and significant deformations. This is particularly the case for red blood cells when they move through our blood vessels or muscle cells during muscle contraction.

Unfortunately, this cellular deformation can be affected and have major consequences. In the case of red blood cells, their capacity for deformation is reduced during their storage in blood bags intended for blood transfusion as well as in a high number of red blood cell diseases. In both cases, the red blood cells are quickly destroyed in our body and can no longer feed our tissues. Similarly, the lack of muscle cell deformation in Duchenne Muscular Dystrophy causes degeneration of muscle fibers and is accompanied very quickly by muscle weakness and progressive paralysis. In cancer, on the contrary, the tumor cells have an excess of deformability, which contributes to the development of metastases.

If we want to improve the conservation of blood bags before transfusion, discover new drugs for the treatment of red blood cell diseases, Duchenne muscular dystrophy and cancer as well as improve the quality of life of patients, it is essential to start by understanding the mechanisms that allow cells to deform.

A series of observations by our group demonstrate that lipids, the major cell membrane constituents, contribute to the deformation of red blood cells and are deregulated during their storage in blood bags and in red blood cell diseases, including hereditary spherocytosis and elliptocytosis. This expertise acquired on the red blood cell, the development and validation of tools for the study of membrane lipids and the acquisition of super-resolution microscopes have enabled us to recently expand our research to breast cancer as well as myogenesis and Duchenne muscular dystrophy.

Cell deformation is critical for numerous pathophysiological processes. Our group explores how plasma membrane biophysical properties contribute with the cytoskeleton and membrane bending proteins to cell deformation and how this interplay is deregulated in diseases. This is the first step before considering to use membrane properties as diagnostic biomarker and/or manipulation for therapeutical benefit.

In their environment, cells face a variety of stimuli and stresses inducing cell deformation. Typical examples are shear stress by squeezing of red blood cells (RBCs) in the narrow pores of spleen sinusoïds, stretching of muscle cells during contraction or pressure exerted by tumors on surrounding cells. We aim at elucidating how plasma membrane lipid composition and biophysical properties contribute to cell deformation, as a prerequisite towards understanding diseases.

We mainly use RBCs, as the simplest and best-characterized human cell model with remarkable deformability. Using high-resolution confocal imaging and atomic force microscopy (coll. D. Alsteens, UCLouvain), we discovered the existence of stable submicrometric lipid domains at the living RBC plasma membrane. Three types of domains coexist, showing differential composition, membrane curvature association, lipid order and role in RBC deformation. Cholesterol-enriched domains contribute to RBC deformation through their gathering in highly curved membrane areas. The two other domains, coenriched in cholesterol and sphingolipids, increase in abundance upon calcium influx and efflux respectively, suggesting they could provide platforms for the recruitment and/or activation of proteins involved in calcium exchanges.

At the end of their lifetime, RBCs become less deformable and lose part of their membrane by extracellular vesicle (EV) release. In blood tubes stored at 4°C, EV release is high and accompanied by the loss of cholesterol-enriched domains, suggesting they could represent sites susceptible to vesiculation. Despite a lower extent of vesiculation, this relationship is also relevant to RBC concentrates intended for blood transfusion (coll. Croix-Rouge de Belgique), opening the possibility of targeting cholesterol to limit EV release in RBC concentrates before transfusion and therefore improving RBC concentrate storage.

Membrane lipid domains and biophysical properties are deregulated in RBC-related diseases, including spherocytosis, elliptocytosis, hypobetalipoproteinemia and neuroacanthocytosis. Extension to erythroleukemia, a rare type of acute myeloid leukemia with poor prognosis (coll. V. Havelange), is ongoing.

We recently started to explore the contribution of plasma membrane lipids for myoblast migration and fusion into myotubes and for breast cancer cell invasion. Both myoblasts and mammary cells exhibit different types of lipid domains with distinct roles in cell migration. Moreover, the comparison of malignant with pre- and non-malignant cells reveals that cholesterol-enriched domains and plasma membrane biophysical properties are deregulated in breast cancer (coll. D. Alsteens) and that the decrease of cholesterol content specifically inhibits invasion of the malignant cells. Our data open the possibility to target cholesterol by a pharmaceutical approach in breast cancer.

Our group works in tandem with the Platform for Imaging Cells and Tissues (PICT). PICT is not only a core facility providing access and training to high-throughput, high-resolution, super-resolution and multiphoton confocal imaging, but also a source of expertise, advice and collaborations within the DDUV Institute, the health research campus of the UCLouvain, as well as national and international partnerships, both academic and industrial. For additional information on equipments and expertise, please see https://www.deduveinstitute.be/pict-platform-imaging-cells-and-tissues


Complete list on PubMed
Donatienne Tyteca
Institut de Duve
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