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Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

View ORCID ProfileJeovanis Gil, Yonghyo Kim, Beáta Szeitz, Viktória Doma, Uğur Çakır, Natália Pinto de Almeida, Yanick Paco Hagemeijer, Victor Guryev, Jenny G Johansson, Yogita Sharma, Indira Pla Parada, Zsolt Horvath, Jéssica de Siqueira Guedes, Gustavo Monnerat, Gabriel Reis Alves Carneiro, Fábio CS Nogueira, Boram Lee, Henriett Oskolas, Enikő Kuroli, Judit Hársing, Yutaka Sugihara, Magdalena Kuras, Roger Appelqvist, Elisabet Wieslander, Gilberto B Domont, Bo Baldetorp, Runyu Hong, Gergely Huszty, Laura Vizkeleti, József Tímár, David Fenyö, Lazaro Hiram Betancourt, Johan Jakobsson, Johan Malm, Aniel Sanchez, A. Marcell Szász, Peter Horvatovich, Melinda Rezeli, Sarolta Kárpáti, György Marko-Varga
doi: https://doi.org/10.1101/2021.04.10.439245
Jeovanis Gil
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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  • ORCID record for Jeovanis Gil
  • For correspondence: jeovanis.gil_valdes@med.lu.se
Yonghyo Kim
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Beáta Szeitz
2Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
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Viktória Doma
3Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
4Second Department of Pathology, Semmelweis University, Budapest, Hungary
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Uğur Çakır
3Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
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Natália Pinto de Almeida
5Clinical Protein Science & Imaging, Department of Biomedical Engineering, Lund University, Lund, Sweden
6Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Yanick Paco Hagemeijer
7European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen,Groningen, The Netherlands
8Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
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Victor Guryev
7European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen,Groningen, The Netherlands
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Jenny G Johansson
9Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Lund University, Lund, Sweden
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Yogita Sharma
9Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Lund University, Lund, Sweden
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Indira Pla Parada
10Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
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Zsolt Horvath
5Clinical Protein Science & Imaging, Department of Biomedical Engineering, Lund University, Lund, Sweden
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Jéssica de Siqueira Guedes
6Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Gustavo Monnerat
6Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Gabriel Reis Alves Carneiro
6Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Fábio CS Nogueira
6Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Boram Lee
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Henriett Oskolas
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Enikő Kuroli
3Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
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Judit Hársing
3Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
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Yutaka Sugihara
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Magdalena Kuras
10Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
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Roger Appelqvist
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Elisabet Wieslander
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Gilberto B Domont
6Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Bo Baldetorp
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Runyu Hong
11Institute for Systems Genetics and Department of Biochemistry and Pharmacology, New York University, Grossman School of Medicine, New York, USA
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Gergely Huszty
12Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
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Laura Vizkeleti
4Second Department of Pathology, Semmelweis University, Budapest, Hungary
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József Tímár
4Second Department of Pathology, Semmelweis University, Budapest, Hungary
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David Fenyö
11Institute for Systems Genetics and Department of Biochemistry and Pharmacology, New York University, Grossman School of Medicine, New York, USA
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Lazaro Hiram Betancourt
1Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Johan Jakobsson
9Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Lund University, Lund, Sweden
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Johan Malm
10Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
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Aniel Sanchez
10Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
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A. Marcell Szász
2Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
13Department of Bioinformatics, Semmelweis University, Budapest, Hungary
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Peter Horvatovich
8Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
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Melinda Rezeli
5Clinical Protein Science & Imaging, Department of Biomedical Engineering, Lund University, Lund, Sweden
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Sarolta Kárpáti
3Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
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György Marko-Varga
5Clinical Protein Science & Imaging, Department of Biomedical Engineering, Lund University, Lund, Sweden
14Chemical Genomics Global Research Lab, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
15st, Tokyo, Japan
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  • Abstract
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Summary

Malignant melanoma (MM) develops from the melanocytes and in its advanced stage is the most aggressive type of skin cancer. Here we report a comprehensive analysis on a prospective cohort study, including non-tumor, primary and metastasis tissues (n=77) with the corresponding plasma samples (n=56) from patients with malignant melanoma. The tumors and surrounding tissues were characterized with a combination of high-throughput analyses including quantitative proteomics, phosphoproteomics, acetylomics, and whole exome sequencing (WES) combined with in-depth histopathology analysis. Melanoma cell proliferation highly correlates with dysregulation at the proteome, at the posttranslational- and at the transcriptome level. Some of the changes were also verified in the plasma proteome. The metabolic reprogramming in melanoma includes upregulation of the glycolysis and the oxidative phosphorylation, and an increase in glutamine consumption, while downregulated proteins involved in the degradation of amino acids, fatty acids, and the extracellular matrix (ECM) receptor interaction. The pathways most dysregulated in MM including the MAP kinases-, the PI3K-AKT signaling, and the calcium homeostasis, are among the most affected by mutations, thus, dysregulation in these pathways can be manifested as drivers in melanoma development and progression.

The phosphoproteome analysis combined with target-based prediction mapped 75% of the human kinome. Melanoma cell proliferation was driven by two key factors: i) metabolic reprogramming leading to upregulation of the glycolysis and oxidative phosphorylation, supported by HIF-1 signaling pathway and mitochondrial translation; and ii) a dysregulation of the immune system response, which was mirrored by immune system processes in the plasma proteome. Regulation of the melanoma acetylome and expression of deacetylase enzymes discriminated between groups based on tissue origin and proliferation, indicating a way to guide the successful use of HDAC inhibitors in melanoma. The disease progression toward metastasis is driven by the downregulation of the immune system response, including MHC class I and II, which allows tumors to evade immune surveillance. Altogether, new evidence is provided at different molecular levels to allow improved understanding of the melanoma progression, ultimately contributing to better treatment strategies.

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Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵17 Senior author

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 11, 2021.
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Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion
Jeovanis Gil, Yonghyo Kim, Beáta Szeitz, Viktória Doma, Uğur Çakır, Natália Pinto de Almeida, Yanick Paco Hagemeijer, Victor Guryev, Jenny G Johansson, Yogita Sharma, Indira Pla Parada, Zsolt Horvath, Jéssica de Siqueira Guedes, Gustavo Monnerat, Gabriel Reis Alves Carneiro, Fábio CS Nogueira, Boram Lee, Henriett Oskolas, Enikő Kuroli, Judit Hársing, Yutaka Sugihara, Magdalena Kuras, Roger Appelqvist, Elisabet Wieslander, Gilberto B Domont, Bo Baldetorp, Runyu Hong, Gergely Huszty, Laura Vizkeleti, József Tímár, David Fenyö, Lazaro Hiram Betancourt, Johan Jakobsson, Johan Malm, Aniel Sanchez, A. Marcell Szász, Peter Horvatovich, Melinda Rezeli, Sarolta Kárpáti, György Marko-Varga
bioRxiv 2021.04.10.439245; doi: https://doi.org/10.1101/2021.04.10.439245
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Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion
Jeovanis Gil, Yonghyo Kim, Beáta Szeitz, Viktória Doma, Uğur Çakır, Natália Pinto de Almeida, Yanick Paco Hagemeijer, Victor Guryev, Jenny G Johansson, Yogita Sharma, Indira Pla Parada, Zsolt Horvath, Jéssica de Siqueira Guedes, Gustavo Monnerat, Gabriel Reis Alves Carneiro, Fábio CS Nogueira, Boram Lee, Henriett Oskolas, Enikő Kuroli, Judit Hársing, Yutaka Sugihara, Magdalena Kuras, Roger Appelqvist, Elisabet Wieslander, Gilberto B Domont, Bo Baldetorp, Runyu Hong, Gergely Huszty, Laura Vizkeleti, József Tímár, David Fenyö, Lazaro Hiram Betancourt, Johan Jakobsson, Johan Malm, Aniel Sanchez, A. Marcell Szász, Peter Horvatovich, Melinda Rezeli, Sarolta Kárpáti, György Marko-Varga
bioRxiv 2021.04.10.439245; doi: https://doi.org/10.1101/2021.04.10.439245

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