Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis.
Kerrie L MarieAntonella SassanoHoward H YangAleksandra M MichalowskiHelen T MichaelTheresa GuoYien Che TsaiAllan M WeissmanMaxwell P LeeLisa M Miller JenkinsM Raza ZaidiEva Pérez-GuijarroChi-Ping DayKris YlayaStephen M HewittNimit L PatelHeinz ArnheiterSean DavisPaul S MeltzerGlenn MerlinoPravin J MishraPublished in: Nature communications (2020)
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.
Keyphrases
- genome wide
- single cell
- rna seq
- mouse model
- squamous cell carcinoma
- gene expression
- small cell lung cancer
- dna methylation
- genome wide identification
- copy number
- poor prognosis
- transcription factor
- binding protein
- magnetic resonance imaging
- case report
- small molecule
- genome wide analysis
- young adults
- computed tomography
- skin cancer
- squamous cell
- amino acid
- replacement therapy
- contrast enhanced