Universität zu Köln

Grothey, Bastian ORCID: 0000-0002-0883-6481, Lyu, Su Ir ORCID: 0009-0002-4125-6048, Quaas, Alexander ORCID: 0000-0002-3537-6011, Simon, Adrian Georg ORCID: 0000-0002-2709-863X, Jung, Jin-On ORCID: 0000-0001-6121-0114, Schröder, Wolfgang ORCID: 0000-0002-8700-069X, Bruns, Christiane J. ORCID: 0000-0001-6590-8181, Schiffmann, Lars M. ORCID: 0000-0002-2320-5004, Popp, Felix C. ORCID: 0000-0002-1690-6777, Schmidt, Thomas ORCID: 0000-0002-7166-3675 and Knipper, Karl ORCID: 0009-0008-7133-3538 (2025). Proteomic characterization of MET-amplified esophageal adenocarcinomas reveals enrichment of alternative splicing- and androgen signaling-related proteins. Cellular and Molecular Life Sciences, 82 (1). pp. 1-13. Springer Nature. ISSN 1420-9071

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Abstract

[Article No. 112] Background: Esophageal adenocarcinomas (EACs) represent an evolving tumor entity with high mortality rates. MET amplification is a recurrent driver in EACs and is associated with decreased patient survival. However, the response to MET inhibitors is limited. Recent studies have identified several mechanisms that lead to resistance against MET inhibitors in different tumor entities. Nonetheless, a characterization of additional vulnerable targets beyond MET has not been conducted in MET-amplified EACs. Methods: In this study, we determined the MET amplification status in a cohort of more than 900 EACs using fluorescence in situ hybridization (FISH) and compared the proteomes of MET-amplified ( n = 20) versus non-amplified tumors ( n = 39) by mass spectrometry. Results: We identified a phenotype, present in almost all MET-amplified tumors, which shows an enrichment of alternative RNA splicing, and androgen receptor signaling proteins, as well as decreased patient survival. Additionally, our analyses revealed a negative correlation between MET expression and patient survival in MET-amplified EACs, indicating biological heterogeneity with clinical relevance despite the presence of MET amplification as the predominant oncogenic driver. Furthermore, quantitative immunohistochemical analysis of the inflammatory tumor microenvironment showed that an increased percentage of M2 macrophages is associated with lower overall survival in MET-amplified EACs. Conclusions: Our results provide valuable insights into possible new therapeutic approaches for MET-amplified EACs for further research.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Grothey, Bastian UNSPECIFIED https://orcid.org/0000-0002-0883-6481 UNSPECIFIED Lyu, Su Ir UNSPECIFIED https://orcid.org/0009-0002-4125-6048 UNSPECIFIED Quaas, Alexander UNSPECIFIED https://orcid.org/0000-0002-3537-6011 UNSPECIFIED Simon, Adrian Georg UNSPECIFIED https://orcid.org/0000-0002-2709-863X UNSPECIFIED Jung, Jin-On UNSPECIFIED https://orcid.org/0000-0001-6121-0114 UNSPECIFIED Schröder, Wolfgang UNSPECIFIED https://orcid.org/0000-0002-8700-069X UNSPECIFIED Bruns, Christiane J. UNSPECIFIED https://orcid.org/0000-0001-6590-8181 UNSPECIFIED Schiffmann, Lars M. UNSPECIFIED https://orcid.org/0000-0002-2320-5004 UNSPECIFIED Popp, Felix C. UNSPECIFIED https://orcid.org/0000-0002-1690-6777 UNSPECIFIED Schmidt, Thomas UNSPECIFIED https://orcid.org/0000-0002-7166-3675 UNSPECIFIED Knipper, Karl UNSPECIFIED https://orcid.org/0009-0008-7133-3538 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-792965
Identification Number:	10.1007/s00018-025-05635-7
Journal or Publication Title:	Cellular and Molecular Life Sciences
Volume:	82
Number:	1
Page Range:	pp. 1-13
Date:	13 March 2025
Publisher:	Springer Nature
ISSN:	1420-9071
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Chirurgie > Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie Faculty of Medicine > Pathologie und Neuropathologie > Institut für Pathologie Faculty of Medicine > Sonstiges > Centrum für integrierte Onkologie (CIO)
Subjects:	Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79296