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Cancer Cell. 2014 Jul 14;26(1):61-76. doi: 10.1016/j.ccr.2014.04.030. Epub 2014 Jun 26.

RAB7 controls melanoma progression by exploiting a lineage-specific wiring of the endolysosomal pathway.

Author information

1
Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
2
Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
3
Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
4
Epithelial Carcinogenesis Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Instituto de Investigación i+12, Hospital 12 de Octubre, Universidad Complutense, Madrid 28041, Spain.
7
Department of Dermatology, University Hospital of Zurich, Zurich 8091, Switzerland.
8
Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: msoengas@cnio.es.

Abstract

Although common cancer hallmarks are well established, lineage-restricted oncogenes remain less understood. Here, we report an inherent dependency of melanoma cells on the small GTPase RAB7, identified within a lysosomal gene cluster that distinguishes this malignancy from over 35 tumor types. Analyses in human cells, clinical specimens, and mouse models demonstrated that RAB7 is an early-induced melanoma driver whose levels can be tuned to favor tumor invasion, ultimately defining metastatic risk. Importantly, RAB7 levels and function were independent of MITF, the best-characterized melanocyte lineage-specific transcription factor. Instead, we describe the neuroectodermal master modulator SOX10 and the oncogene MYC as RAB7 regulators. These results reveal a unique wiring of the lysosomal pathway that melanomas exploit to foster tumor progression.

PMID:
24981740
DOI:
10.1016/j.ccr.2014.04.030
[Indexed for MEDLINE]
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