Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals
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 focu...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-01-01
|
Series: | Biomedicines |
Subjects: | |
Online Access: | https://www.mdpi.com/2227-9059/9/1/79 |
id |
doaj-4f522836841d4fdd87db2194d3c3be0f |
---|---|
record_format |
Article |
spelling |
doaj-4f522836841d4fdd87db2194d3c3be0f2021-01-16T00:02:19ZengMDPI AGBiomedicines2227-90592021-01-019797910.3390/biomedicines9010079Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication SignalsClaudio Tabolacci0Martina Cordella1Sabrina Mariotti2Stefania Rossi3Cinzia Senatore4Carla Lintas5Lauretta Levati6Daniela D’Arcangelo7Antonio Facchiano8Stefania D’Atri9Roberto Nisini10Francesco Facchiano11Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, ItalyDepartment of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, ItalyDepartment of Experimental Medicine, University Campus Bio-Medico, 00128 Rome, ItalyLaboratory of Molecular Oncology, IDI-IRCCS, 00167 Rome, ItalyLaboratory of Molecular Oncology, IDI-IRCCS, 00167 Rome, ItalyLaboratory of Molecular Oncology, IDI-IRCCS, 00167 Rome, ItalyLaboratory of Molecular Oncology, IDI-IRCCS, 00167 Rome, ItalyDepartment of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, ItalyThe 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-γ, 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.https://www.mdpi.com/2227-9059/9/1/79melanomaBRAF inhibitors resistancesecretory signalsinflammationbasigin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Claudio Tabolacci Martina Cordella Sabrina Mariotti Stefania Rossi Cinzia Senatore Carla Lintas Lauretta Levati Daniela D’Arcangelo Antonio Facchiano Stefania D’Atri Roberto Nisini Francesco Facchiano |
spellingShingle |
Claudio Tabolacci Martina Cordella Sabrina Mariotti Stefania Rossi Cinzia Senatore Carla Lintas Lauretta Levati Daniela D’Arcangelo Antonio Facchiano Stefania D’Atri Roberto Nisini Francesco Facchiano Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals Biomedicines melanoma BRAF inhibitors resistance secretory signals inflammation basigin |
author_facet |
Claudio Tabolacci Martina Cordella Sabrina Mariotti Stefania Rossi Cinzia Senatore Carla Lintas Lauretta Levati Daniela D’Arcangelo Antonio Facchiano Stefania D’Atri Roberto Nisini Francesco Facchiano |
author_sort |
Claudio Tabolacci |
title |
Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals |
title_short |
Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals |
title_full |
Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals |
title_fullStr |
Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals |
title_full_unstemmed |
Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals |
title_sort |
melanoma cell resistance to vemurafenib modifies inter-cellular communication signals |
publisher |
MDPI AG |
series |
Biomedicines |
issn |
2227-9059 |
publishDate |
2021-01-01 |
description |
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-γ, 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. |
topic |
melanoma BRAF inhibitors resistance secretory signals inflammation basigin |
url |
https://www.mdpi.com/2227-9059/9/1/79 |
work_keys_str_mv |
AT claudiotabolacci melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT martinacordella melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT sabrinamariotti melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT stefaniarossi melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT cinziasenatore melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT carlalintas melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT laurettalevati melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT danieladarcangelo melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT antoniofacchiano melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT stefaniadatri melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT robertonisini melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals AT francescofacchiano melanomacellresistancetovemurafenibmodifiesintercellularcommunicationsignals |
_version_ |
1724336236572704768 |