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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • RNA Interference
  • SOXE Transcription Factors / genetics
  • SOXE Transcription Factors / metabolism
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy
  • Time Factors
  • Transfection
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Biomarkers, Tumor
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • SOX10 protein, human
  • SOXE Transcription Factors
  • rab7 protein
  • rab GTP-Binding Proteins