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Proteomics identifies markers of MAPKi resistance offering new therapeutic strategies in melanoma- Cytoplasmic (cyt), nuclear (ne) and secreted (sn) proteins of BRAFi resistant melanoma cells

ABSTRACT: MAPK inhibitors (MAPKi) show outstanding clinical response rates in melanoma patients harbouring BRAF mutations, but resistance is common. High-throughput, subcellular proteome analyses at two different MS laboratories and RNA-seq on two panels of primary melanoma cells that were either sensitive or MAPKi resistant, revealed that only fifteen proteins were sufficient to discriminate between resistant and sensitive cells. The two proteins with the highest discriminatory power were PTRF and IGFBP7, both highly upregulated in the resistant cells. They were associated with epithelial-mesenchymal transition (EMT) and are mechanistically linked. Knock-out of PTRF revealed targets involved in lysosomal activation, endocytosis, pH regulation, EMT, TGFbeta signalling and cell migration and adhesion. In addition, immunohistochemistry on patient samples showed that PTRF and IGFBP7 expression levels were significant biomarkers of poor progression free survival under MAPKi treatment. A drug screen of MAPKi resistant cells using a 960-compound kinase modulator library identified two lead compounds that were effective in targeting MAPKi resistant cells.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Skin

DISEASE(S): Melanoma

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD005433 | Pride | 2019-07-23

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	MM121224_BRAFi_resistant_cyt_1.mgf	Mgf
	MM121224_BRAFi_resistant_cyt_1.mzid.gz	Mzid
	MM121224_BRAFi_resistant_cyt_1.pride.mgf.gz	Mgf
	MM121224_BRAFi_resistant_cyt_1.pride.mztab.gz	Mztab
	MM121224_BRAFi_resistant_cyt_1.raw	Raw

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Project description:Brain metastases of melanoma are associated with therapy resistance and poor prognosis. It is not fully understood whether and how the selection of cells capable of metastasizing into the brain is accompanied by the establishment of specific features. For the investigation of these questions, we made use of previously described xenograft mouse models for primary human melanoma cells distinguishing cutaneous from cerebellar metastases from the same genetic background. Previous experiments suggested that cultured cells derived from these xenografts still maintain properties characteristic for the microenvironment of the originating metastases. Such corresponding pairs of metastatic cells were obtained from four individual donors, resulting in eight cell-lines presently investigated with regard to molecular properties characteristic for metastasis. Label free proteome profiling revealed significant alterations when comparing corresponding pairs of cutaneous and cerebellar metastases from the same donor. Molecules previously associated with metastasis such as cell adhesion molecules, immune regulators, epithelial mesenchymal transition markers, stem cell markers, redox regulators and cytokines were found differently expressed. This was also observed with regard to eicosanoids considered relevant for metastasis such as PGE2 and 12-HETE. However, no commonalities in the molecular characteristics of cerebellar metastases were identified in all four donors. Multiparametric morphological analysis of cells also revealed alterations associated with the kind of metastases, while lacking uniformity. In conclusion, here we describe that xenografted melanoma cells derived from two different microenvironments, i.e. cutaneous and cerebellar metastases, display significant alterations in the expression of molecules associated with metastastic properties. The observed lack of uniformity suggests that metastatic cells may find individual strategies to adapt to their microenvironmental challenges accompanied by the establishment of individual cell characteristics.

Dataset Information

Proteomics identifies markers of MAPKi resistance offering new therapeutic strategies in melanoma- Cytoplasmic (cyt), nuclear (ne) and secreted (sn) proteins of BRAFi resistant melanoma cells

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