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Targeting β-catenin using XAV939 nanoparticle promotes immunogenic cell death and suppresses conjunctival melanoma
Ferrin Antony1, Xuejia Kang2, Chetan Pundkar1
1Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
Abstract:
Many tumors dysregulate Wnt/β-catenin pathway to promote stem-cell-like phenotype, tumorigenesis, immunosuppression, and resistance to targeted cancer immunotherapies. Therefore, targeting this pathway is a promising therapeutic approach to suppress tumor progression and elicit robust anti-tumor immunity. In this study, using a nanoparticle formulation for XAV939 (XAV-Np), a tankyrase inhibitor that promotes β-catenin degradation, we investigated the effect of β-catenin inhibition on melanoma cell viability, migration, and tumor progression using a mouse model of conjunctival melanoma. XAV-Nps were uniform and displayed near-spherical morphology with size stability for upto 5 days. We show that XAV-Np treatment of mouse melanoma cells significantly suppresses cell viability, tumor cell migration, and tumor spheroid formation compared to control nanoparticle (Con-Np) or free XAV939-treated groups. Further, we demonstrate that XAV-Np promotes immunogenic cell death (ICD) of tumor cells with a significant extracellular release or expression of ICD molecules, including high mobility group box 1 protein (HMGB1), calreticulin (CRT), and adenosine triphosphate (ATP). Finally, we show that local intra-tumoral delivery of XAV-Nps during conjunctival melanoma progression significantly suppresses tumor size and conjunctival melanoma progression compared to Con-Nps-treated animals. Collectively, our data suggest that selective inhibition of β-catenin in tumor cells using nanoparticle-based targeted delivery represents a novel approach to suppress tumor progression through increased tumor cell ICD.
Insights
Targeting the Wnt/β-catenin pathway with nanoparticle-delivered XAV939 (XAV-Np) inhibits melanoma progression. XAV-Np suppresses tumor cell viability and migration, promoting immunogenic cell death and reducing tumor size in a mouse model.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- The Wnt/β-catenin pathway is frequently dysregulated in tumors, promoting cancer stemness, growth, and immune evasion.
- Inhibition of this pathway is a potential strategy to halt tumor progression and enhance anti-tumor immunity.
- Targeting Wnt/β-catenin may overcome resistance to cancer immunotherapies.
Purpose of the Study:
- To investigate the therapeutic potential of nanoparticle-formulated XAV939 (XAV-Np) for inhibiting conjunctival melanoma.
- To assess the effects of β-catenin inhibition on melanoma cell viability, migration, and tumor progression in a preclinical mouse model.
- To evaluate XAV-Np's ability to induce immunogenic cell death (ICD) and suppress tumor growth.
Main Methods:
- Development of a nanoparticle formulation for the tankyrase inhibitor XAV939 (XAV-Np).
- In vitro assessment of XAV-Np effects on mouse melanoma cell viability, migration, and spheroid formation.
- In vivo evaluation of intra-tumoral XAV-Np delivery in a conjunctival melanoma mouse model.
- Analysis of ICD marker expression (HMGB1, CRT, ATP) following XAV-Np treatment.
Main Results:
- XAV-Np exhibited uniform morphology and stability.
- XAV-Np significantly suppressed melanoma cell viability, migration, and spheroid formation compared to controls.
- XAV-Np treatment induced immunogenic cell death (ICD) with increased release of ICD molecules.
- Intra-tumoral delivery of XAV-Np significantly reduced tumor size and progression in vivo.
Conclusions:
- Nanoparticle-mediated delivery of XAV939 (XAV-Np) is an effective strategy for targeting β-catenin in melanoma.
- XAV-Np suppresses tumor progression by inhibiting cell viability and migration while promoting ICD.
- This approach holds promise for developing novel cancer therapies against conjunctival melanoma.
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