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Updated: Aug 12, 2025
Real-time Imaging of Leukotriene B4 Mediated Cell Migration and BLT1 Interactions with β-arrestin
Published on: December 23, 2010
ACKR3 promotes CXCL12/CXCR4-mediated cell-to-cell-induced lymphoma migration through LTB4 production
Paola Antonello1,2, Diego U Pizzagalli1,3, Mathilde Foglierini1,4
1Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.
Abstract:
Chemotaxis is an essential physiological process, often harnessed by tumors for metastasis. CXCR4, its ligand CXCL12 and the atypical receptor ACKR3 are overexpressed in many human cancers. Interfering with this axis by ACKR3 deletion impairs lymphoma cell migration towards CXCL12. Here, we propose a model of how ACKR3 controls the migration of the diffused large B-cell lymphoma VAL cells in vitro and in vivo in response to CXCL12. VAL cells expressing full-length ACKR3, but not a truncated version missing the C-terminus, can support the migration of VAL cells lacking ACKR3 (VAL-ko) when allowed to migrate together. This migration of VAL-ko cells is pertussis toxin-sensitive suggesting the involvement of a Gi-protein coupled receptor. RNAseq analysis indicate the expression of chemotaxis-mediating LTB4 receptors in VAL cells. We found that LTB4 acts synergistically with CXCL12 in stimulating the migration of VAL cells. Pharmacologic or genetic inhibition of BLT1R markedly reduces chemotaxis towards CXCL12 suggesting that LTB4 enhances in a contact-independent manner the migration of lymphoma cells. The results unveil a novel mechanism of cell-to-cell-induced migration of lymphoma.
Insights
Tumor cell migration is influenced by ACKR3 and CXCL12. This study reveals that LTB4 synergizes with CXCL12, enhancing lymphoma cell migration via a novel contact-independent mechanism.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Chemotaxis is crucial for tumor metastasis, with the CXCR4/CXCL12/ACKR3 axis frequently overexpressed in cancers.
- ACKR3 deletion has been shown to impair lymphoma cell migration towards CXCL12, highlighting its role in cancer progression.
Purpose of the Study:
- To elucidate the mechanism by which ACKR3 influences the migration of diffuse large B-cell lymphoma (DLBCL) VAL cells in response to CXCL12.
- To investigate the synergistic role of LTB4 and CXCL12 in DLBCL cell chemotaxis.
Main Methods:
- Utilized VAL cells expressing full-length or truncated ACKR3, and ACKR3-knockout (VAL-ko) cells for migration assays.
- Employed pertussis toxin sensitivity assays to identify G-protein coupled receptor involvement.
- Conducted RNAseq analysis to identify chemotaxis-mediating receptors and pharmacologic/genetic inhibition of BLT1R.
Main Results:
- Full-length ACKR3 expression in VAL cells supports the migration of VAL-ko cells towards CXCL12, dependent on Gi-protein signaling.
- RNAseq revealed expression of LTB4 receptors in VAL cells.
- LTB4 synergizes with CXCL12 to stimulate VAL cell migration, and BLT1R inhibition significantly reduces chemotaxis.
Conclusions:
- ACKR3 plays a key role in mediating DLBCL cell migration, potentially through cell-to-cell interactions.
- LTB4 acts synergistically with CXCL12 in a contact-independent manner to enhance lymphoma cell migration.
- These findings uncover a novel mechanism of cell-to-cell-induced migration in lymphoma, offering potential therapeutic targets.
