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Updated: Sep 26, 2025
Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
XIAP promotes melanoma growth by inducing tumour neutrophil infiltration
Mila Daoud1,2,3, Pia Nora Broxtermann1,2,3, Fabian Schorn1,2,3
1Faculty of Medicine and University Hospital of Cologne, Institute for Molecular Immunology, University of Cologne, Cologne, Germany.
Abstract:
Elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been frequently reported in malignant melanoma suggesting that XIAP renders apoptosis resistance and thereby supports melanoma progression. Independent of its anti-apoptotic function, XIAP mediates cellular inflammatory signalling and promotes immunity against bacterial infection. The pro-inflammatory function of XIAP has not yet been considered in cancer. By providing detailed in vitro analyses, utilising two independent mouse melanoma models and including human melanoma samples, we show here that XIAP is an important mediator of melanoma neutrophil infiltration. Neutrophils represent a major driver of melanoma progression and are increasingly considered as a valuable therapeutic target in solid cancer. Our data reveal that XIAP ubiquitylates RIPK2, involve TAB1/RIPK2 complex and induce the transcriptional up-regulation and secretion of chemokines such as IL8, that are responsible for intra-tumour neutrophil accumulation. Alteration of the XIAP-RIPK2-TAB1 inflammatory axis or the depletion of neutrophils in mice reduced melanoma growth. Our data shed new light on how XIAP contributes to tumour growth and provides important insights for novel XIAP targeting strategies in cancer.
Insights
The X-linked inhibitor of apoptosis protein (XIAP) promotes melanoma growth by increasing neutrophil infiltration via the RIPK2-TAB1 pathway. Targeting XIAP or neutrophils may offer new cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- X-linked inhibitor of apoptosis protein (XIAP) is linked to melanoma progression and apoptosis resistance.
- XIAP also regulates inflammatory signaling, a role not previously explored in cancer.
- Neutrophils are key drivers of melanoma progression and potential therapeutic targets.
Purpose of the Study:
- To investigate the role of XIAP's pro-inflammatory function in melanoma.
- To elucidate the mechanism by which XIAP influences neutrophil infiltration in melanoma.
- To explore XIAP-targeting strategies for melanoma treatment.
Main Methods:
- In vitro analyses using melanoma cell lines.
- Studies utilizing two independent mouse melanoma models.
- Examination of human melanoma samples.
Main Results:
- XIAP mediates melanoma neutrophil infiltration by ubiquitylating RIPK2 within the TAB1/RIPK2 complex.
- This interaction leads to increased transcription and secretion of chemokines like IL8, promoting neutrophil accumulation.
- Inhibition of the XIAP-RIPK2-TAB1 axis or neutrophil depletion significantly reduced melanoma growth in mice.
Conclusions:
- XIAP plays a critical role in promoting melanoma growth through neutrophil recruitment.
- The XIAP-RIPK2-TAB1 inflammatory axis is a novel pathway contributing to tumor progression.
- Targeting XIAP or neutrophils presents a promising therapeutic strategy for melanoma.
