Targeting cholesterol transport in circulating melanoma cells to inhibit metastasis

Yu Chi Chen, Raghavendra Gowda, Raymond K. Newswanger, Patrick Leibich, Barry Fell, Gerson Rosenberg, Gavin P. Robertson

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)541-552
Number of pages12
JournalPigment Cell and Melanoma Research
Volume30
Issue number6
DOIs
StatePublished - Nov 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology

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