Chemokine Receptors as targets for cancer and inflammation therapy

Research Summary

Through their interactions with G protein-coupled receptors, the chemokines have a key role in a broad array of biological responses that include cell polarisation and movement, immune and inflammatory responses, haematopoiesis, tumour rejection and prevention of HIV-1 infection.

Research Lines

Cell migration involves myriad signaling proteins and receptors that act coordinately to activate intracellular pathways and promote polarized cell states and directional migration. To migrate directionally in response to external stimuli, the internal machinery of cells needs to be spatially organized, which involves the integration of biochemical and mechanical factors to generate force in a specific direction to move the cell forward. Chemokine receptors are membrane-expressed seven-transmembrane receptors linked to G proteins. Through interaction with the corresponding ligands, they induce a wide variety of cellular responses including cell polarization, movement, immune and inflammatory responses, as well as prevention of HIV-1 infection. For achieving their function, chemokine receptors undergo ligand-dependent conformational changes that are influenced by the local cellular microenvironment.

Using quantitative single-molecule spatio-dynamic imaging, our group studies the dynamics of the chemokine receptors at the cell membrane and the factors that influence it. We observed how the maintenance of correct actin dynamics in migrating cells is essential for the formation of large receptor nano-clusters in response to the ligand and its role for a correct sensing of the chemoattractant gradients. We have determined that altered cluster formation, using natural mutant chemokine receptors or altering the lipid composition of the cell membrane, results in the inability of these cells to correctly sense chemokine gradients.  Using in silico strategies and in vitro assays we have also designed some allosteric modulators that block receptor clustering and directed cell migration without altering neither ligand binding nor other signaling events. The evidence indicates that receptor clustering can be exploited as therapeutic target in inflammatory diseases and cancer.

In addition, our group is also involved in studying the effect of distinct mediators in reprograming/training of macrophages to improve resolution of some disease.

Migration of HeLa cells treated with vehicle (DMSO) or with the selected small compounds (AGR1.131 or AGR1.137) as indicated, on μ-chambers in response to a CXCL12. Figure shows representative spider plots with the trajectories of tracked cells migrating along the gradient (black) or moving in the opposite direction (red).

Surface representation of CXCR4 and the clefts identified between transmembrane (TM) region V and VI.  The protein structure is shown in gray, with TMV and TMVI colored in blue and pink respectively. The small compounds AGR1.135 and AGR1.137 binding, were identified by SurfNet software, are shown in orange and green respectively. Volumes for each cavity are measured (Å3)

Group Members

Funding

Our research is funded by national and international institutions as indicated below. For more details, please check the general Funding Section at the CNB website.

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