New paper by the Thelen Lab
on Thursday, June 29, 2017
The paper published in the journal Oncotarget unveils an important role of the atypical chemokine receptor ACKR3 in tissue infiltration of diffuse large B cell lymphoma (DLBCL). The receptor is expressed in a variety of DLBCL. The group focused on human VAL cells, which express functional ACKR3 on the plasma membrane. Receptor scavenging activity was shown by CXCL12 internalization and antibody uptake.
|Brain sections showing meningeal infiltration pattern with foci of beginning parenchymal invasion only in the presence of ACKR3. Magnification 4x and 10x, as indicated|
The group of Marcus Thelen then used the CRISPR/Cas9 system to edit the genome of VAL cells eliminating the gene of ACKR3. In vitro transwell assays through endothelial monolayers were used to measure CXCL12-meiated migration via the chemokine receptor CXCR4. Ablation of ACKR3 or attenuation with the competitive agonist CCX771 markedly inhibited the chemotactic response of VAL cells to CXCL12. They went on and tested the role of ACKR3 expression in vivo. They fund, that functional expression of ACKR3 in DLBCL cells was necessary for colonization of draining lymph nodes in a localized subcutaneous lymphoma model. A more striking effect of ACKR3 ablation was observed in a disseminated lymphoma model. In presence of ACKR3 cells massively invaded lymphoid organs, such as bone marrow and spleen and also the brain, in absence of ACKR3, cells essentially failed in infiltrating these organs. The results unveil ACKR3 as a potential therapeutic target for DLBCL.
ACKR3 expression on diffuse large B cell lymphoma is required for tumor spreading and tissue infiltration
V. Puddinu, S. Casella, E. Radice, S. Thelen, S. Dirnhofer, F. Bertoni, M. Thelen
in Oncotarget (2017)