PhD Scientific Days 2021

Budapest, 7-8 July 2021

PO_II_L: Pathology and Oncology II. Lectures

Metabolic Reprogramming and Immune System Modulation in Metastatic Melanoma - a Proteogenomic Study

Beáta Szeitz1, Jeovanis Gil2, Yonghyo Kim2, Viktória Doma3,4, Uğur Çakır3, Natália Pinto de Almeida5,6, Yanick Paco Hagemeijer7,8, Victor Guryev7, Jenny G Johansson9, Yogita Sharma9, Indira Pla Parada10, Zsolt Horvath5, Jéssica de Siqueira Guedes6, Gustavo Monnerat6, Gabriel Reis Alves Carneiro6, Fábio CS Nogueira6, Boram Lee2, Henriett Oskolas2, Enikő Kuroli3, Judit Hársing3, Yutaka Sugihara2, Magdalena Kuras10, Roger Appelqvist2, Elisabet Wieslander2, Gilberto B Domont6, Bo Baldetorp2, Runyu Hong11, Gergely Huszty12, Laura Vizkeleti4, József Tímár4, David Fenyö11, Lazaro Hiram Betancourt2, Johan Jakobsson9, Johan Malm10, Aniel Sanchez10, A. Marcell Szász1,13, Peter Horvatovich8, Melinda Rezeli5, Sarolta Kárpáti3, and György Marko-Varga5,14,15

1- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
2- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
3- Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
4- Second Department of Pathology, Semmelweis University, Budapest, Hungary
5- Clinical Protein Science & Imaging, Department of Biomedical Engineering, Lund University, Lund, Sweden
6- Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
7- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
8- Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
9- Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Lund University, Lund, Sweden
10- Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
11- Institute for Systems Genetics and Department of Biochemistry and Pharmacology, New York University, Grossman School of Medicine, New York, USA
12- Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
13- Department of Bioinformatics, Semmelweis University, Budapest, Hungary
14- Chemical Genomics Global Research Lab, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
15- 1st Department of Surgery, Tokyo Medical University, Tokyo, Japan

Text of the abstract

Introduction: Melanoma is one of the most aggressive forms of skin cancer, with a relatively high incidence rate in Europe. Recent progress in targeted therapy and immunotherapy has decreased the mortality rate even at more advanced disease stages, however, due to its heterogeneous nature and largely unpredictable metastasis development, it still represents a major challenge in the clinic.
Aims: The study aims at the proteogenomic characterization of melanoma-related samples to highlight dysregulated processes occurring with disease progression.
Methods: 47 melanoma patients were investigated in this prospective study. 77 tissue samples (including non-tumor, primary tumor, and metastasis) were analyzed using quantitative proteomics, phosphoproteomics, acetylomics, and whole exome sequencing (WES). RNA sequencing data on melanoma from TCGA was integrated for a more in-depth analysis.
Result: Tumor proliferation status, inferred from the abundance of the minichromosome maintenance complex, was found to be correlated with similar dysregulated processes on each molecular layer. Proteomic data showed that high proliferation rate is accompanied by the upregulation of glycolysis and oxidative phosphorylation, as well as the HIF-1 signaling pathway and mitochondrial translation. Interactors or regulators of the immune system, signaling pathway and the calcium homeostasis were frequently mutated according to WES data. A combined analysis of proteomics and transcriptomics revealed that high proliferative tumors repress the immune system-related pathways, as the way to evade immune surveillance. Phosphoproteomics and acetylomics revealed functional insights into key proliferation related enzymes, as well as the regulation of the antigen processing and presentation machinery, mainly via acetylation.
Conclusion: The study provides further evidence that melanoma proliferation is supported by: 1) an altered energy metabolism to avoid nutrient deficit, and 2) by the dysregulation of the immune system response to avoid tumor suppressor mechanisms.
Funding: Supported by the Berta Kamprad Foundation and Thermo Fischer Scientific.

University and Doctoral School

Semmelweis University, Doctoral School of Pathological Sciences