RAB7 Controls Melanoma Progression by Exploiting a Lineage-Specific Wiring of the Endolysosomal Pathway

• Published in: Cancer cell 2014-07, Vol.26 (1), p.61-76
• Main Authors: Alonso-Curbelo, Direna, Riveiro-Falkenbach, Erica, Pérez-Guijarro, Eva, Cifdaloz, Metehan, Karras, Panagiotis, Osterloh, Lisa, Megías, Diego, Cañón, Estela, Calvo, Tonantzin G., Olmeda, David, Gómez-López, Gonzalo, Graña, Osvaldo, Sánchez-Arévalo Lobo, Víctor Javier, Pisano, David G., Wang, Hao-Wei, Ortiz-Romero, Pablo, Tormo, Damià, Hoek, Keith, Rodríguez-Peralto, José L., Joyce, Johanna A., Soengas, María S.
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Line, Tumor; Cell Lineage; Cell Movement; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Lysosomes - enzymology; Melanoma - enzymology; Melanoma - genetics; Melanoma - mortality; Melanoma - secondary; Melanoma - therapy; Mice; Neoplasm Invasiveness; Neoplasm Staging; Protein Transport; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; RNA Interference; Skin Neoplasms - enzymology; Skin Neoplasms - genetics; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Skin Neoplasms - therapy; SOXE Transcription Factors - genetics; SOXE Transcription Factors - metabolism; Time Factors; Transfection
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2014.04.030

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. [Display omitted] •Melanoma-restricted lysosomal gene cluster uncovers tumor-type-specific roles of RAB7•RAB7-controlled pathways selectively modulate melanoma cell phenotypes•RAB7 is an early-induced melanoma driver that defines patient prognosis•MYC and SOX10 regulate RAB7 in an oncogene- and lineage-dependent manner, respectively Alonso-Curbelo et al. identify a unique dependency in melanoma on the small GTPase RAB7 due to regulation by both oncogenic and lineage-specific factors. RAB7 controls melanoma cell phenotype and represents a possible vulnerability that can be therapeutically exploited.