PhD Scientific Days 2022

Budapest, 6-7 July 2022

Pathology and Oncology I. (Poster discussion will take place in the Aula during the Coffee Break)

Proteomic Profiling of Primary Tumors and Corresponding Brain Metastases of Surgically Treated Lung Adenocarcinoma Patients Reveal Increased Inter-tumoral Heterogeneity

Zsolt Megyesfalvi1,2,3, Nicole Woldmar4,5, Anna Schwendenwein3, Magdalena Kuras6, Beáta Szeitz7, Kristiina Boettiger3, Anna Tisza2,8, Viktória László2,3, Lilla Reiniger8,9, Attila G. Bagó10, Zoltán Szállási9,11,12, Judit Moldvay2, Attila Marcell Szász2,7, Johan Malm6, Péter Horvatovich13, Luciana Pizzatti5, Gilberto B. Domont14, Ferenc Rényi-Vámos1,2, Konrad Hoetzenecker3, Mir Alireza Hoda3, György Marko-Varga4, Karin Schelch3, Melinda Rezeli4*, Balázs Döme1,2,3*

1- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary;
2- National Koranyi Institute of Pulmonology, Budapest, Hungary
3- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;
4- Department of Biomedical Engineering, Lund University, Lund, Sweden;
5- Laboratory of Molecular Biology and Proteomics of Blood/LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;
6- Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden;
7- Department of Bioinformatics, Semmelweis University, Budapest, Hungary;
8- Department of Pathology and Experimental Cancer Research Semmelweis University, Budapest, Hungary;
9- Department of Pathology, Forensic and Insurance Medicine, MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences;
10- Department of Neurooncology, National Institute of Clinical Neurosciences, Budapest, Hungary, Budapest, Hungary;
11- Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA;
12- Danish Cancer Society Research Center, Copenhagen, Denmark;
13- Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands;
14- Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;
*These authors share the last authorship

Text of the abstract

Introduction: Brain metastasis (BM), the most common distant metastasis in lung adenocarcinoma (LADC), has a significant negative impact on patients’ outcomes. Therefore, novel treatment and follow-up strategies are urgently needed in these patients.

Aims: Our aim was to investigate the inter-tumoral heterogeneity in brain metastatic LADC patients with proteomic approaches, as well as to assess the impact of the existing proteomic pattern on the timing of BMs.

Method: Proteomic profiling was conducted on 20 surgically resected primary- and brain metastatic LADC samples via label-free shotgun proteomics. Large-scale protein identification and quantitation were followed by in-depth bioinformatical and statistical analyses. Proteomic data were correlated with clinicopathological parameters and the timing of BMs.

Results: Out of the 6,821 proteins quantified and identified in the tumor samples, 1,496 proteins were differentially expressed between primary LADCs and corresponding BMs. 1D annotation enrichment analysis revealed that pathways associated with the immune system, cell-cell/matrix interactions and migration were predominantly activated in the primary tumors, whereas pathways related to metabolism, translation or vesicle formation were overrepresented in the metastatic tumors. When comparing fast- vs. slow-progressing patients, we found 454 and 298 differentially expressed proteins in the primary tumors and BMs, respectively. Specifically, we found that metabolic pathways and the ribosome pathway were upregulated in the fast-progressing patients (vs. slow-progressing individuals), whereas, cell-cell interaction- and immune system-related pathways were downregulated in these patients and in those with multiple BMs.

Conclusion: By shedding light on the specific proteomic profiles of primary and brain metastatic LADCs, our results might provide insights into the biological processes involved in the metastatic spread, and moreover, might contribute to the development of personalized follow-up strategies in the clinics.

Funding: Zs.M. was supported by the UNKP‐ 20‐ 3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary.

E-mail: megyesfalvi.zsolt@semmelweis-univ.hu
University and Doctoral School: Semmelweis University – Károly Rácz Doctoral School of Clinical Medicine
Supervisor: Dr. Balázs Döme