title: RAB7 controls melanoma progression by exploiting a lineage-specific wiring of the endolysosomal pathway.
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.
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Direna
authors: D
authors: Alonso-Curbelo
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Erica
authors: E
authors: Riveiro-Falkenbach
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Eva
authors: E
authors: Pérez-Guijarro
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Metehan
authors: M
authors: Cifdaloz
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Panagiotis
authors: P
authors: Karras
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Lisa
authors: L
authors: Osterloh
authors: Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Diego
authors: D
authors: Megías
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Estela
authors: E
authors: Cañón
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Tonantzin G
authors: TG
authors: Calvo
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: David
authors: D
authors: Olmeda
authors: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Gonzalo
authors: G
authors: Gómez-López
authors: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Osvaldo
authors: O
authors: Graña
authors: Epithelial Carcinogenesis Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Víctor Javier
authors: VJ
authors: Sánchez-Arévalo Lobo
authors: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: David G
authors: DG
authors: Pisano
authors: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Hao-Wei
authors: HW
authors: Wang
authors: Instituto de Investigación i+12, Hospital 12 de Octubre, Universidad Complutense, Madrid 28041, Spain.
authors: Pablo
authors: P
authors: Ortiz-Romero
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Damià
authors: D
authors: Tormo
authors: Department of Dermatology, University Hospital of Zurich, Zurich 8091, Switzerland.
authors: Keith
authors: K
authors: Hoek
authors: Instituto de Investigación i+12, Hospital 12 de Octubre, Universidad Complutense, Madrid 28041, Spain.
authors: José L
authors: JL
authors: Rodríguez-Peralto
authors: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Johanna A
authors: JA
authors: Joyce
authors: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: msoengas@cnio.es.
authors: María S
authors: MS
authors: Soengas
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000556:secondary / Q000628:therapy; D051379:Mice; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D014408:Biomarkers, Tumor; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D020691:rab GTP-Binding Proteins