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Feeder-free Derivation of Melanocytes from Human Pluripotent Stem Cells
Published on: March 3, 2016
Multiepitope tissue analysis reveals SPPL3-mediated ADAM10 activation as a key step in the transformation of
Christian Ostalecki1, Jung-Hyun Lee1, Jochen Dindorf1
1Department of Dermatology, University Hospital Erlangen, Translational Research Center, Schwabachanlage 12, 91054 Erlangen, Germany.
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.
Insights
Cancer transformation involves protein cooperation. Mutant BRAF drives ADAM10 activation via SPPL3, a key event inhibited by PTEN, offering new insights into melanoma development.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cancer evolution relies on cooperating proteins, not just mutations.
- Understanding protein expression profiles (PEPs) is crucial for identifying malignant transformation drivers.
Purpose of the Study:
- To identify key protein expression events during melanoma development using multiepitope ligand cartography (MELC).
- To elucidate the role of ADAM10 activation in cancer transformation.
Main Methods:
- Analysis of protein expression profiles (PEPs) in nevi and melanomas using MELC technology.
- Coculture experiments with melanoma cells and keratinocytes.
- Investigating the mechanism of ADAM10 activation by SPPL3 and its regulation by PTEN.
Main Results:
- PEPs differed between nevi and melanomas, with gradual changes in associated keratinocytes.
- Mutant BRAFV600E triggered SPPL3-mediated ADAM10 activation, a critical transformation event.
- SPPL3-mediated ADAM10 activation occurred in endosomal compartments and was inhibited by PTEN.
Conclusions:
- Systematic tissue antigen analysis complements genomic approaches for cancer development insights.
- SPPL3-mediated ADAM10 activation is a key step in melanoma transformation.
- PTEN acts as a tumor suppressor by inhibiting ADAM10 activation.
