PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Nitschkowski, D.* ; Vierbuchen, T.* ; Heine, H.* ; Behrends, J.* ; Reiling, N.* ; Reck, M.* ; Rabe, K.F.* ; Kugler, C.* ; Ammerpohl, O.* ; Drömann, D.* ; Muley, T.* ; Kriegsmann, M.* ; Stathopoulos, G.T. ; Arendt, K.A.M. ; Goldmann, T.* ; Marwitz, S.*

SMAD2 linker phosphorylation impacts overall survival, proliferation, TGFβ1-dependent gene expression and pluripotency-related proteins in NSCLC.

Br. J. Cancer, DOI: 10.1038/s41416-025-02970-1 (2025)
Publ. Version/Full Text DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
BACKGROUND: We investigated the impact of SMAD2 linker phosphorylation (pSMAD2L) on overall and disease-free survival, signal transduction, as well as cancer-related processes in non-small cell lung cancer (NSCLC). METHODS: We generated A549 cells constitutively lacking pSMAD2L (A549Lsub) to gain mechanistic insights and stimulated NSCLC cell lines with inhibitors against cell cycle-associated kinases or TGFβ1. In addition, we analysed SMAD2 and pSMAD2L in alveolar epithelial cells type 2 from tumour-free lung tissue as well as in benign and malignant T cells by Western blotting. Furthermore, pSMAD2L-positive tumours and immune cells were analysed in an NSCLC patient cohort (n = 316) using multiplex immunofluorescence. RESULTS: In NSCLC cell lines and benign T cells, pSMAD2L was expressed in a mitosis-dependent manner. Loss of pSMAD2L (A549Lsub) had an anti-proliferative effect, slowed migration, and increased alternatively spliced short SMAD2 (SMAD2ΔE3). The gene signature in A549Lsub was associated with developmental and morphogenetic processes and redirected canonical TGFβ1-dependent signalling. By contrast, SMAD2ΔE3 was absent in benign T cells but present in malignant T lymphoblasts. NSCLC patients with low pSMAD2L+ tumour cell density had a poorer prognosis, whereas low pSMAD2L+ immune cell density favoured overall and disease-free survival. CONCLUSIONS: pSMAD2L antagonises anti-proliferative canonical TGFβ-signalling in NSCLC and redirects TGFβ1-dependent gene expression, whereas loss of pSMAD2L enhances SMAD2ΔE3 and affects pluripotency-associated proteins in vitro. In NSCLC patients, pSMAD2L cell density influences disease-free and overall survival in a spatially distinct manner.
Impact Factor
Scopus SNIP
Altmetric
6.800
0.000
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Keywords Cell Lung-cancer; Tgf-beta; Metastasis; Resistance; Pathways; Regions; Stage
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 0007-0920
e-ISSN 1532-1827
Journal British Journal of Cancer BJC
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Lung Research
PSP Element(s) G-501600-003
Grants Projekt DEAL
German Center for Lung Research (DZL)
DOI 10.1038/s41416-025-02970-1
WOS ID 001480461200001
Scopus ID 105004051927
PubMed ID 40319202
Erfassungsdatum 2025-05-11
[➜Report correction]