Project number 5

Search for biomarkers and therapeutic targets within the biomolecular composition of plasma membranes of metastatic melanoma cells

A cardinal feature of melanoma is its metastatic propensity. Paucity of insights into the genetic events that drive metastasis has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. Under specific conditions (i.e. hypoxia, …) melanoma cells undergo reversible “phenotype switching/reprogramming”, including dramatic changes in the composition of cell surface proteins, that confer them with increased invasive and migratory capacity. There is also increasing evidence that disturbed vesicular transport plays key roles in the progression and spreading of cancer. Although several of these specific changes have been documented, a systematic and comprehensive analysis of the biomolecular composition of plasma membranes during metastatic reprogramming of cancer cells is still lacking. Moreover a causative link between these changes and cancer cell dissemination remains to be firmly established.
 To fill in this gap we will use superparamagnetic iron oxide nanoparticles (SPIONs) to isolate plasma membranes of matching non-invasive and invasive melanoma cells to a yield and purity that allows quantitative proteomics and lipidomics and the generation of full inventories of the biomolecular changes occurring at the cell surface during metastatic ‘reprogramming’ events. SPION synthesis and plasma membrane isolations will be carried out in the lab of Prof. Annaert with support of VIB proteomics expertise center.
In a second phase we will exploit the OMICS data to search for new bona fide membrane-associated proteins, lipids and pathways that drive melanoma progression and metastasis. The availability of somatic cell gene delivery mouse model of melanoma in the lab of Prof. Marine will allow rapid validation of selected alterations in an in vivo context.
Knowing that 2/3 of the current drugs target surface molecules, this integrative approach may therefore lead to the identification of novel melanoma-specific biomarkers and selective therapeutic targets.

Keywords
cancer, melanoma, metastasis, plasma membrane omics, superparamagnetic iron oxide nanoparticles

Supervisors
Wim Annaert, VIB Center for the Biology of Disease, KU Leuven, Leuven
Jean-Christophe Marine, VIB Lab for Molecular Cancer Biology, KU Leuven, Leuven