Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis

Kerrie L. Marie, Antonella Sassano, Howard H. Yang, Aleksandra M. Michalowski, Helen T. Michael, Theresa Guo, Yien Che Tsai, Allan M. Weissman, Maxwell P. Lee, Lisa M. Jenkins, M. Raza Zaidi, Eva Pérez-Guijarro, Chi-Ping Day, Kris Ylaya, Stephen M. Hewitt, Nimit L. Patel, Heinz Arnheiter, Sean Davis, Paul S. Meltzer, Glenn Merlino () and Pravin J. Mishra
Additional contact information
Kerrie L. Marie: National Institutes of Health
Antonella Sassano: National Institutes of Health
Howard H. Yang: National Institutes of Health
Aleksandra M. Michalowski: National Institutes of Health
Helen T. Michael: National Institutes of Health
Theresa Guo: National Institutes of Health
Yien Che Tsai: National Cancer Institute
Allan M. Weissman: National Cancer Institute
Maxwell P. Lee: National Institutes of Health
Lisa M. Jenkins: National Institutes of Health
M. Raza Zaidi: Lewis Katz School of Medicine at Temple University
Eva Pérez-Guijarro: National Institutes of Health
Chi-Ping Day: National Institutes of Health
Kris Ylaya: National Institutes of Health
Stephen M. Hewitt: National Institutes of Health
Nimit L. Patel: Leidos Biomedical Research Inc.
Heinz Arnheiter: National Institute of Health
Sean Davis: National Institutes of Health
Paul S. Meltzer: National Institutes of Health
Glenn Merlino: National Institutes of Health
Pravin J. Mishra: National Institutes of Health

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.

Date: 2020
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DOI: 10.1038/s41467-019-14085-2

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