@article{1fba2facce2a4d408d042a9056a1ef73,
title = "Proteomic analysis of brain metastatic lung adenocarcinoma reveals intertumoral heterogeneity and specific alterations associated with the timing of brain metastases",
abstract = "Background: Brain metastases are associated with considerable negative effects on patients{\textquoteright} 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.",
keywords = "brain metastasis, clinical proteomics, intertumoral heterogeneity, lung adenocarcinoma",
author = "N. Woldmar and A. Schwendenwein and M. Kuras and B. Szeitz and K. Boettiger and A. Tisza and V. L{\'a}szl{\'o} and L. Reiniger and Bag{\'o}, \{A. G.\} and Z. Sz{\'a}ll{\'a}si and J. Moldvay and Sz{\'a}sz, \{A. M.\} and J. Malm and P. Horvatovich and L. Pizzatti and Domont, \{G. B.\} and F. R{\'e}nyi-V{\'a}mos and K. Hoetzenecker and Hoda, \{M. A.\} and G. Marko-Varga and K. Schelch and Z. Megyesfalvi and M. Rezeli and B. D{\"o}me",
note = "Funding Information: This work was supported by the Hungarian National Research, Development and Innovation Office [grant numbers KH130356, KKP126790 to BD; 2020-1.1.6-J{\"O}V{\H o}, TKP2021-EGA-33 and FK-143751 to BD and ZM; KTIA\_NAP\_13-2014-0021, NAP2-2017-1.2.1-NKP-00002 to J Mo and ZS; K129065 to J Mo; KNN121510 to AMS). BD was also supported by the Austrian Science Fund [grant numbers FWF I3522, FWF I3977, FWF I4677). ZM was supported by the UNKP-20-3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary , and by the Hungarian Respiratory Society (MPA \#2020). ZM is recipient of the ILCF Young Investigator Grant. VL is a recipient of the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology. MR acknowledges funding from the Royal Physiographic Society of Lund and the Mrs. Berta Kamprad{\textquoteright}s Cancer Foundation [grant number FBKS-2020-22-(291)]. We thank the Brazilian foundation CAPES for the scholarship to NW [grant number CAPES 88887.130697]. PH was supported by the Netherlands X-omics Initiative (NWO, project number 184.034.019). Funding Information: This work was done under the auspices of a Memorandum of Understanding between the European Cancer Moonshot Center in Lund and the U.S. National Cancer Institute's International Cancer Proteogenome Consortium (ICPC). ICPC encourages international cooperation among institutions and nations in proteogenomic cancer research in which proteogenomic datasets are made available to the public. The study was conducted under the Memorandum of Understanding between the Federal University of Rio de Janeiro, Brazil, and Lund University, Sweden. This work was supported by the Hungarian National Research, Development and Innovation Office [grant numbers KH130356, KKP126790 to BD; 2020-1.1.6-J{\"O}V{\H o}, TKP2021-EGA-33 and FK-143751 to BD and ZM; KTIA\_NAP\_13-2014-0021, NAP2-2017-1.2.1-NKP-00002 to J Mo and ZS; K129065 to J Mo; KNN121510 to AMS). BD was also supported by the Austrian Science Fund [grant numbers FWF I3522, FWF I3977, FWF I4677). ZM was supported by the UNKP-20-3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary, and by the Hungarian Respiratory Society (MPA \#2020). ZM is recipient of the ILCF Young Investigator Grant. VL is a recipient of the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology. MR acknowledges funding from the Royal Physiographic Society of Lund and the Mrs. Berta Kamprad's Cancer Foundation [grant number FBKS-2020-22-(291)]. We thank the Brazilian foundation CAPES for the scholarship to NW [grant number CAPES 88887.130697]. PH was supported by the Netherlands X-omics Initiative (NWO, project number 184.034.019). The authors have declared no conflicts of interest. The mass spectrometry proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD027259. All samples were collected under informed written consent (ethical approval, 2521-0/2010-1018EKU). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2023",
month = feb,
doi = "10.1016/j.esmoop.2022.100741",
language = "English",
volume = "8",
journal = "ESMO Open",
issn = "2059-7029",
publisher = "BMJ Publishing Group",
number = "1",
}