Research ArticleCancer

Multiepitope tissue analysis reveals SPPL3-mediated ADAM10 activation as a key step in the transformation of melanocytes

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Sci. Signal.  14 Mar 2017:
Vol. 10, Issue 470, eaai8288
DOI: 10.1126/scisignal.aai8288

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Mapping protein drivers of melanoma

Genomic profiling technology has identified purported driver mutations in various cancers, but it is most often the proteins that drive tumor development and present therapeutic targets. Furthermore, tumor genomic profiling misses the contribution of cells of the tumor microenvironment to tumor progression. Using multiepitope ligand cartography on human skin samples, Ostalecki et al. identified changes in protein abundance and subcellular localization in melanocytes and keratinocytes that were associated with various stages of melanoma development. The findings revealed the transfer of a peptidase-metalloproteinase pair from early-stage BRAF-mutant/PTEN-null melanoma cells to adjacent normal keratinocytes through cell contact. The recipient keratinocytes exhibited altered protein abundance and secretion. Inhibiting this intercellular mode of communication and its effects might be therapeutic in melanoma patients.

Abstract

The evolution of cancer is characterized by the appearance of specific mutations, but these mutations are translated into proteins that must cooperate to induce malignant transformation. Using a systemic approach with the multiepitope ligand cartography (MELC) technology, we analyzed protein expression profiles (PEPs) in nevi and BRAFV600E-positive superficial spreading melanomas (SSMs) from patient tissues to identify key transformation events. The PEPs in nevi and SSMs differed predominantly in the abundance of specific antigens, but the PEPs of nevi- and melanoma-associated keratinocytes gradually changed during the transformation process. A stepwise change in PEP with similar properties occurred in keratinocytes cocultured with melanoma cells. Analysis of the individual steps indicated that activation of the metalloproteinase ADAM10 by signal peptide peptidase–like 3 (SPPL3) triggered by mutant BRAFV600E was a critical transformation event. SPPL3-mediated ADAM10 activation involved the translocation of SPPL3 and ADAM10 into Rab4- or Rab27-positive endosomal compartments. This endosomal translocation, and hence ADAM10 activation, was inhibited by the presence of the tumor suppressor PTEN. Our findings suggest that systematic tissue antigen analysis could complement whole-genome approaches to provide more insight into cancer development.

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