Dynamic Regulation of Endolysosomal Programs Drives Melanoma Progression

Although a myriad of genetic and epigenetic alterations have been implicated in tumorigenesis, drivers of lineage-specific tumor progression remain poorly understood. In melanoma, the rheostat protein microphthalmia-associated transcription factor (MITF) has been characterized as a lineage-specific regulator of tumor development, but is overexpressed in only a fraction of melanoma cases. Alonso-Curbelo and colleagues performed gene ontology analysis of transcriptional data sets and identified the small GTPase RAB7 as part of an enriched lysosomal gene signature in melanoma but not other tumor types. Depletion or inhibition of RAB7 impaired autophagosome–endosome degradation and selectively reduced the proliferation and tumorigenic potential of melanoma cells. This phenotype was accompanied by decreased expression of genes involved in cell-cycle progression, including E2F1 target genes. However, despite decreased cell growth, RAB7-depleted melanoma cells displayed increased invasive and migratory properties and enhanced expression of prometastatic factors, including multiple lysosomal cathepsins, suggesting that RAB7 may have a dual role in melanoma progression. RAB7 expression was highest in the early radial growth phase of melanoma, decreased at the invasive front of vertical growth phase melanomas, and was upregulated again at distal metastatic sites. In addition, low RAB7 expression in primary melanomas was correlated with increased metastatic risk and reduced overall survival, supporting the idea that RAB7 is dynamically regulated as tumors progress. This regulation was independent of MITF but dependent on the MYC oncogene and the melanocyte-specific transcription factor SRY (sex determining region Y)-box 10 (SOX10), which were coordinately expressed with RAB7 in primary melanoma samples and were required for its upregulation in early melanoma. These findings demonstrate how the rewiring of a lineage-specific developmental pathway contributes to tumor progression. Furthermore, these results offer RAB7 as a clinical biomarker of patient prognosis and suggest that RAB7-mediated vesicular trafficking may facilitate selective drug delivery in melanoma.

Alonso-Curbelo D, Riveiro-Falkenbach E, Pérez-Guijarro E, Cifdaloz M, Karras P, Osterloh L, et al. RAB7 controls melanoma progression by exploiting a lineage-specific wiring of the endolysosomal pathway. Cancer Cell 2014 Jun 26 [Epub ahead of print].