Proteomic analysis of brain metastatic lung adenocarcinoma reveals intertumoral heterogeneity and specific alterations associated with the timing of brain metastases

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N. Woldmar¹  A. Schwendenwein³  M. Kuras⁴  B. Szeitz⁵  K. Boettiger³  A. Tisza⁶  V. László³  L. Reiniger⁷  A.G. Bagó⁹  Z. Szállási⁸  J. Moldvay⁶  A.M. Szász⁶  J. Malm⁴  P. Horvatovich^1,13  L. Pizzatti²  G.B. Domont^1,14  F. Rényi-Vámos⁶  K. Hoetzenecker³  M.A. Hoda³  G. Marko-Varga¹  K. Schelch³  Z. Megyesfalvi³  M. Rezeli¹  B. Döme³ 

[1] Department of Biomedical Engineering, Lund University;Laboratory of Molecular Biology and Proteomics of Blood/LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro;Department of Thoracic Surgery, Medical University Vienna;Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö;Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University;National Korányi Institute of Pulmonology;Department of Pathology and Experimental Cancer Research, Semmelweis University;Department of Pathology, Forensic and Insurance Medicine, MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences;Department of Neurooncology, National Institute of Clinical Neurosciences;Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School;Danish Cancer Society Research Center;Department of Bioinformatics, Semmelweis University;Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen;Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro;Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University

关键词: lung adenocarcinoma;    brain metastasis;    clinical proteomics;    intertumoral heterogeneity;   

DOI  :  10.1016/j.esmoop.2022.100741

学科分类：社会科学、人文和艺术（综合）

来源: BMJ Publishing Group

【 摘 要 】

Background Brain metastases are associated with considerable negative effects on patients' outcome in lung adenocarcinoma (LADC). Here, we investigated the proteomic landscape of primary LADCs and their corresponding brain metastases.Materials and methods Proteomic profiling was conducted on 20 surgically resected primary and brain metastatic LADC samples via label-free shotgun proteomics. After sample processing, peptides were analyzed using an Ultimate 3000 pump coupled to a QExactive HF-X mass spectrometer. Raw data were searched using PD 2.4. Further data analyses were carried out using Perseus, RStudio and GraphPad Prism. Proteomic data were correlated with clinical and histopathological parameters and the timing of brain metastases. Mass spectrometry-based proteomic data are available via ProteomeXchange with identifier PXD027259.Results Out of the 6821 proteins identified and quantified, 1496 proteins were differentially expressed between primary LADCs and corresponding brain metastases. 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- versus slow-progressing patients, we found 454 and 298 differentially expressed proteins in the primary tumors and brain metastases, respectively. Metabolic reprogramming and ribosomal activity were prominently up-regulated in the fast-progressing patients (versus slow-progressing individuals), whereas expression of cell-cell interaction- and immune system-related pathways was reduced in these patients and in those with multiple brain metastases.Conclusions This is the first comprehensive proteomic analysis of paired primary tumors and brain metastases of LADC patients. Our data suggest a malfunction of cellular attachment and an increase in ribosomal activity in LADC tissue, promoting brain metastasis. The current study provides insights into the biology of LADC brain metastases and, moreover, might contribute to the development of personalized follow-up strategies in LADC.

【 授权许可】

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