Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-14085-2
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Funding
- NCI Intramural Research Program of the NIH
- NCI
- NIH/NCI [K22CA163799]
- HHMI Research Scholars Program, Howard Hughes Medical Institute
- NIH
- University of Maryland, College Park
- National Cancer Institute
- NATIONAL CANCER INSTITUTE [ZIABC009392, ZIABC011167, ZICBC011430, ZIHBC011703, ZIABC008756, ZICBC011638, ZIABC011091] Funding Source: NIH RePORTER
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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.
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