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A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Targeting cholesterol transport in circulating melanoma cells to inhibit metastasis
Yu-Chi Chen1, Raghavendra Gowda1, Raymond K Newswanger2
1Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Abstract:
Despite recent breakthroughs in targeted- and immune-based therapies, rapid development of drug resistance remains a hurdle for the long-term treatment of patients with melanoma. Targeting metastatically spreading circulating tumor cells (CTCs) may provide an additional approach to manage melanoma. This study investigates whether targeting cholesterol transport in melanoma CTCs can retard metastasis development. Nanolipolee-007, the liposomal form of leelamine, reduced melanoma metastasis in both a novel in vitro flow system mimicking the circulating system and in experimental as well as spontaneous animal metastasis models, irrespective of the BRAF mutational status of the CTCs. Leelamine led to cholesterol trapping in lysosomes, which subsequently shut down receptor-mediated endocytosis, endosome trafficking, and inhibited the major oncogenic signaling cascades important for survival such as the AKT pathway. As pAKT is important in CTC survival, inhibition by targeting cholesterol metabolism led to apoptosis, suggesting this approach might be particularly effective for those CTCs having high levels of pAKT to aid survival in the circulation system.
Insights
Targeting cholesterol transport in melanoma circulating tumor cells (CTCs) with Nanolipolee-007 effectively reduced metastasis. This approach inhibits key survival pathways, offering a new strategy against melanoma drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Drug resistance limits melanoma treatment efficacy.
- Targeting circulating tumor cells (CTCs) offers a novel therapeutic strategy.
- Cholesterol transport's role in melanoma metastasis requires further investigation.
Purpose of the Study:
- To investigate targeting cholesterol transport in melanoma CTCs to inhibit metastasis.
- To evaluate the efficacy of Nanolipolee-007 (leelamine liposomal form) against melanoma metastasis.
Main Methods:
- Utilized a novel in vitro flow system mimicking circulation.
- Tested Nanolipolee-007 in experimental and spontaneous animal metastasis models.
- Analyzed the impact of leelamine on cellular cholesterol, endocytosis, and signaling pathways.
Main Results:
- Nanolipolee-007 significantly reduced melanoma metastasis in vitro and in vivo.
- Efficacy was independent of BRAF mutational status.
- Leelamine caused lysosomal cholesterol trapping, inhibiting endocytosis and AKT signaling, leading to apoptosis.
Conclusions:
- Targeting cholesterol transport is a promising strategy to impede melanoma metastasis.
- Nanolipolee-007 demonstrates potential as an anti-metastatic agent for melanoma.
- Inhibition of cholesterol metabolism and AKT pathway offers a new therapeutic avenue for melanoma, especially in CTCs with high pAKT levels.
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