RT Journal Article
SR Electronic
T1 Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.10.439245
DO 10.1101/2021.04.10.439245
A1 Jeovanis Gil
A1 Yonghyo Kim
A1 Beáta Szeitz
A1 Viktória Doma
A1 Uğur Çakır
A1 Natália Pinto de Almeida
A1 Yanick Paco Hagemeijer
A1 Victor Guryev
A1 Jenny G Johansson
A1 Yogita Sharma
A1 Indira Pla Parada
A1 Zsolt Horvath
A1 Jéssica de Siqueira Guedes
A1 Gustavo Monnerat
A1 Gabriel Reis Alves Carneiro
A1 Fábio CS Nogueira
A1 Boram Lee
A1 Henriett Oskolas
A1 Enikő Kuroli
A1 Judit Hársing
A1 Yutaka Sugihara
A1 Magdalena Kuras
A1 Roger Appelqvist
A1 Elisabet Wieslander
A1 Gilberto B Domont
A1 Bo Baldetorp
A1 Runyu Hong
A1 Gergely Huszty
A1 Laura Vizkeleti
A1 József Tímár
A1 David Fenyö
A1 Lazaro Hiram Betancourt
A1 Johan Jakobsson
A1 Johan Malm
A1 Aniel Sanchez
A1 A. Marcell Szász
A1 Peter Horvatovich
A1 Melinda Rezeli
A1 Sarolta Kárpáti
A1 György Marko-Varga
YR 2021
UL http://biorxiv.org/content/early/2021/04/11/2021.04.10.439245.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.