Dataset Information

Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals.

ABSTRACT: The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the interplay between vemurafenib-resistant melanoma cells and the tumor microenvironment. We found that vemurafenib-resistant melanoma cells can influence dendritic cell (DC) maturation by modulating their activation and cytokine production. In particular, human DCs exposed to conditioned medium (CM) from vemurafenib-resistant melanoma cells produced higher levels of pro-inflammatory cytokines-that potentially facilitate melanoma growth-than DCs exposed to CM derived from parental drug-sensitive cells. Bioinformatic analysis performed on proteins identified by mass spectrometry in the culture medium from vemurafenib-sensitive and vemurafenib-resistant melanoma cells suggests a possible involvement of the proteasome pathway. Moreover, our data confirm that BRAFi-resistant cells display a more aggressive phenotype compared to parental ones, with a significantly increased production of interferon-?, interleukin-8, vascular-endothelial growth factor, CD147/basigin, and metalloproteinase 2 (MMP-2). Plasma levels of CD147/basigin and MMP-2 were also measured before the start of therapy and at disease progression in a small group of melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib. A significant increment in CD147/basigin and MMP-2 was observed in all patients at the time of treatment failure, strengthening the hypothesis that CD147/basigin might play a role in BRAFi resistance.

SUBMITTER: Tabolacci C

PROVIDER: S-EPMC7830125 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals.

Tabolacci Claudio C Cordella Martina M Mariotti Sabrina S Rossi Stefania S Senatore Cinzia C Lintas Carla C Levati Lauretta L D'Arcangelo Daniela D Facchiano Antonio A D'Atri Stefania S Nisini Roberto R Facchiano Francesco F

Biomedicines 20210115 1

The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the inter ...[more]

PMID: 33467521

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Project description:Inter-cellular and inter-kingdom signaling systems of various levels of complexity regulate pathogenic and mutualistic interactions between bacteria, parasites, and fungi and animal and plant hosts. Inter-kingdom interactions between mutualistic bacteria such as rhizobia and legumes during nodulation and between fungi and plants during mycorrhizal associations, are characterized by the extensive exchange of molecular signals, which allow nitrogen and phosphate assimilation, respectively. A novel aspect of this signaling exchange is the existence of specific structures, the exosomes, that carry important molecules that shape the plant-pathogen interactions. Exosomes contain a wide array of molecules, such as lipids, proteins, messenger RNA, and microRNAs, that play important roles in cell-to-cell communication in animal and plant cells by affecting gene expression and other physiological activity in distant cells within the same organism (e.g., during cancer metastases and neuron injuries). In plant cells, it has been recently reported that exosomes go beyond organism boundaries and inhibit a pathogenic interaction in plants. Plant produce and send exosomes loaded with specific small miRNA which inhibit the pathogen infection, but the pathogen can also produce exosomes carrying pro-pathogenic proteins and microRNAs. Therefore, exosomes are the important bridge regulating the signal exchange. Exosomes are small membrane-bound vesicles derived from multivesicular bodies (MVBs), which carries selected cargos from the cytoplasm (protein, lipids, and microRNAs) and under certain circumstances, they fuse with the plasma membrane, releasing the small vesicles as cargo-carrying exosomes into the extracellular space during intercellular and inter-kingdom communication. Animal and plant proteomic studies have demonstrated that tetraspanin proteins are an integral part of exosome membranes, positioning tetraspanins as essential components for endosome organization, with key roles in membrane fusion, cell trafficking, and membrane recognition. We discuss the similarities and differences between animal tetraspanins and plant tetraspanins formed during plant-microbe interactions and their potential role in mutualistic communication.

Dataset Information

Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals.

Publications

Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals.

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