PhD Scientific Days 2021

PO_II_L: Pathology and Oncology II. Lectures

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

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